Montelukast Chewable
Tablets
Generic Name: montelukast sodium
Dosage Form: tablet, chewable
INDICATIONS & USAGE
Asthma
Montelukast sodium chewable tablets are indicated
for the prophylaxis and chronic treatment of asthma in adults and pediatric
patients 2 years of age and older.
Exercise-Induced Bronchoconstriction
(EIB)
Montelukast sodium chewable tablets are indicated
for prevention of exercise-induced bronchoconstriction (EIB) in patients 6
years of age and older.
Allergic Rhinitis
Montelukast sodium chewable tablets are indicated
for the relief of symptoms of seasonal allergic rhinitis in patients 2 years of
age and older and perennial allergic rhinitis in patients 2 years of age
and older.
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DOSAGE & ADMINISTRATION
Asthma
Montelukast sodium chewable tablets should be taken
once daily in the evening. The following doses are recommended:
For adults and adolescents 15 years of age and older: one 10-mg tablet.
For pediatric patients 6 to 14 years of age: one 5-mg chewable tablet.
For pediatric patients 2 to 5 years of age: one 4-mg chewable tablet.
Safety and effectiveness in pediatric patients less than 12 months of age with
asthma have not been established.
There have been no clinical trials in patients with asthma to evaluate the
relative efficacy of morning versus evening dosing. The pharmacokinetics of
montelukast are similar whether dosed in the morning or evening. Efficacy has
been demonstrated for asthma when montelukast was administered in the evening
without regard to time of food ingestion.
Exercise-lnduced Bronchoconstriction
(EIB)
For prevention of EIB,a single dose of montelukast
sodium chewable tablet should be taken at least 2 hours before exercise.
The following doses are recommended:
For adults and adolescents 15 years of age and older: one 10-mg tablet.
For pediatric patients 6 to 14 years of age: one 5-mg chewable tablet.
An additional dose of montelukast sodium chewable tablets should not be taken
within 24 hours of a previous dose. Patients already taking montelukast sodium chewable
tablets daily for another indication (including chronic asthma) should not take
an additional dose to prevent EIB. All patients should have available for
rescue a short-acting β-agonist.Safety and efficacy in patients younger than 6
years of age
have not been established. Daily administration of montelukast sodium chewable
tablets for the chronic treatment of asthma has not been established to prevent
acute episodes of EIB.
Allergic Rhinitis
For allergic rhinitis, montelukast sodium chewable tablets
should be taken once daily. Efficacy was demonstrated for seasonal allergic
rhinitis when montelukast was administered in the morning or the evening
without regard to time of food ingestion. The time of administration may be
individualized to suit patient needs.
The following doses for the treatment of symptoms of seasonal allergic rhinitis
are recommended:
For adults and adolescents 15 years of age and older: one 10-mg tablet.
For pediatric patients 6 to 14 years of age: one 5-mg chewable tablet.
For pediatric patients 2 to 5 years of age: one 4-mg chewable tablet.
Safety and effectiveness in pediatric patients younger than 2 years of age with
seasonal allergic rhinitis have not been established.
The following doses for the treatment of symptoms of perennial allergic
rhinitis are recommended:
For adults and adolescents 15 years of age and older: one 10-mg tablet.
For pediatric patients 6 to 14 years of age: one 5-mg chewable tablet.
For pediatric patients 2 to 5 years of age: one 4-mg chewable tablet.
Safety and effectiveness in pediatric patients younger than 6 months of age
with perennial allergic rhinitis have not been established.
Asthma and Allergic Rhinitis
Patients with both asthma and allergic rhinitis
should take only one montelukast sodium chewable tablets dose daily in the
evening.
DOSAGE FORMS & STRENGTHS
•Montelukast Sodium (equivalent to 4-mg
montelukast) Chewable Tablets are light pink colored, speckled, oval, biconvex
shaped, chewable tablets debossed with 'I' on one side and '112' on the
other side.
•Montelukast Sodium (equivalent to 5-mg montelukast) Chewable Tablets are light
pink colored, speckled, round, biconvex shaped, chewable tablets debossed with
'I' on one side and '113' on the other side.
Contraindications
•Hypersensitivity to any component of this product.
Warnings and Precautions
Acute Asthma
Montelukast sodium is not indicated for use in the
reversal of bronchospasm in acute asthma attacks, including status
asthmaticus.Patients should be advised to have appropriate rescue medication
available.Therapy with montelukast sodium can be continued during acute
exacerbations of asthma.Patients who have exacerbations of asthma after
exercise should have available for rescue a short-acting inhaled β-agonist.
Concomitant Corticosteroid Use
While the dose of inhaled corticosteroid may be
reduced gradually under medical supervision, Montelukast sodium should not be
abruptly substituted for inhaled or oral corticosteroids.
Aspirin Sensitivity
Patients with known aspirin sensitivity should
continue avoidance of aspirin or non-steroidal anti-inflammatory agents while
taking montelukast sodium. Although montelukast sodium is effective in
improving airway function in asthmatics with documented aspirin sensitivity, it
has not been shown to truncate bronchoconstrictor response to aspirin and other
non-steroidal anti-inflammatory drugs in aspirin-sensitive asthmatic
patients [see Clinical Studies (14.1)].
Neuropsychiatric Events
Neuropsychiatric events have been
reported in adult, adolescent, and pediatric patients taking montelukast
sodium. Post-marketing reports with montelukast sodium use include
agitation, aggressivebehavior or hostility, anxiousness,
depression, disorientation, disturbance in attention, dream abnormalities,
hallucinations, insomnia, irritability, memory impairment, restlessness, somnambulism,
suicidal thinking and behavior (including suicide), tic, and tremor. The
clinical details of some post-marketing reports involving montelukast sodium
appear consistent with a drug-induced effect.
Patients and prescribers should be alert for neuropsychiatric events. Patients
should be instructed to notify their prescriber if these changes occur.
Prescribers should carefully evaluate the risks and benefits of continuing
treatment with montelukast sodium if such events occur [see
Adverse Reactions (6.2)].
Eosinophilic Conditions
Patients with asthma on therapy with montelukast
sodium may present with systemic eosinophilia, sometimes presenting with
clinical features of vasculitis consistent with Churg-Strauss syndrome, a
condition which is often treated with systemic corticosteroid therapy. These
events have been sometimes associated with the reduction of oral corticosteroid
therapy. Physicians should be alert to eosinophilia, vasculitic rash, worsening
pulmonary symptoms, cardiac complications, and/or neuropathy presenting in
their patients. A causal association between montelukast sodium and these
underlying conditions has not been established [see
Adverse Reactions (6.2)].
Phenylketonuria
Phenylketonuric patients should be informed that
the 4-mg and 5-mg chewable tablets contain phenylalanine (a component of
aspartame), 0.674 and 0.842 mg per 4-mg and 5-mg chewable tablet,
respectively.
Adverse Reactions
Clinical Trials Experience
Because clinical trials are conducted under widely
varying conditions, adverse reaction rates observed in the clinical trials of a
drug cannot be directly compared to rates in the clinical trials of another
drug and may not reflect the rates observed in clinical practice. In the
following description of clinical trials experience, adverse reactions are
listed regardless of causality assessment.
The most common adverse reactions (incidence ≥5% and greater than placebo;
listed in descending order of frequency) in controlled clinical trials were:
upper respiratory infection, fever, headache, pharyngitis, cough, abdominal
pain, diarrhea, otitis media, influenza, rhinorrhea, sinusitis, otitis.Adults
and Adolescents 15 Years of Age and Older with Asthma
Montelukast sodium has been evaluated for safety in approximately 2950 adult
and adolescent patients 15 years of age and older in clinical trials. In
placebo-controlled clinical trials, the following adverse experiences reported
with montelukast sodium occurred in greater than or equal to 1% of patients and
at an incidence greater than that in patients treated with placebo:Table
1: Adverse Experiences Occurring in ≥1% of Patients with an Incidence Greater
than that in Patients Treated with Placebo
|
|
Montelukast Sodium
10 mg/day
|
Placebo
|
|
(%)
|
(%)
|
|
(n=1955)
|
(n=1180)
|
|
Body As A Whole
|
|
|
|
Pain, abdominal
|
2.9
|
2.5
|
|
Asthenia/fatigue
|
1.8
|
1.2
|
|
Fever
|
1.5
|
0.9
|
|
Trauma
|
1
|
0.8
|
|
Digestive System Disorders
|
|
|
|
Dyspepsia
|
2.1
|
1.1
|
|
Pain, dental
|
1.7
|
1
|
|
Gastroenteritis,
infectious
|
1.5
|
0.5
|
|
Nervous
System/Psychiatric
|
|
|
|
Headache
|
18.4
|
18.1
|
|
Dizziness
|
1.9
|
1.4
|
|
Respiratory
System Disorders
|
|
|
|
Influenza
|
4.2
|
3.9
|
|
Cough
|
2.7
|
2.4
|
|
Congestion, nasal
|
1.6
|
1.3
|
|
Skin/Skin
Appendages Disorder
|
|
|
|
Rash
|
1.6
|
1.2
|
|
Laboratory
Adverse Experiences*
|
|
|
|
ALT increased
|
2.1
|
2
|
|
AST increased
|
1.6
|
1.2
|
|
Pyuria
|
1
|
0.9
|
*Number of patients tested (montelukast sodium and
placebo, respectively): ALT and AST, 1935, 1170; pyuria, 1924, 1159.
The frequency of less common adverse events was
comparable between montelukast sodium and placebo.
The safety profile of montelukast sodium,when administered as a single dose for
prevention of EIB in adult and adolescent patients 15 years of age and older,
was consistent with the safety profile previously described for montelukast
sodium.
Cumulatively, 569 patients were treated with montelukast sodium for at least 6
months, 480 for one year, and 49 for two years in clinical trials. With
prolonged treatment, the adverse experience profile did not significantly
change.
Pediatric Patients 6 to 14 Years of Age with Asthma
Montelukast sodium has been evaluated for safety in 476 pediatric patients 6 to
14 years of age. Cumulatively, 289 pediatric patients were treated with
montelukast sodium for at least 6 months, and 241 for one year or longer in
clinical trials. The safety profile of montelukast sodium in the 8-week,
double-blind, pediatric efficacy trial was generally similar to the adult
safety profile. In pediatric patients 6 to 14 years of age receiving
montelukast sodium, the following events occurred with a frequency ≥2% and more
frequently than in pediatric patients who received placebo: pharyngitis,
influenza, fever, sinusitis, nausea, diarrhea, dyspepsia, otitis, viral
infection, and laryngitis. The frequency of less common adverse events was
comparable between montelukast sodium and placebo. With prolonged treatment,
the adverse experience profile did not significantly change.
The safety profile of montelukast sodium, when administered as a single dose
for prevention of EIB in pediatric patients 6 years of age and older, was
consistent with the safety profile previously described for montelukast sodium.
In studies evaluating growth rate, the safety profile in these pediatric
patients was consistent with the safety profile previously described for
montelukast sodium. In a 56-week, double-blind study evaluating growth rate in
pediatric patients 6 to 8 years of age receiving montelukast sodium, the
following events not previously observed with the use of montelukast sodium in
this age group occurred with a frequency ≥2% and more frequently than in
pediatric patients who received placebo: headache, rhinitis (infective),
varicella, gastroenteritis, atopic dermatitis, acute bronchitis, tooth
infection, skin infection, and myopia.
Pediatric Patients 2 to 5 Years of Age with Asthma
Montelukast sodium has been evaluated for safety in 573 pediatric patients 2 to
5 years of age in single- and multiple-dose studies. Cumulatively, 426
pediatric patients 2 to 5 years of age were treated with montelukast sodium for
at least 3 months, 230 for 6 months or longer, and 63 patients for one year or
longer in clinical trials. In pediatric patients 2 to 5 years of age receiving
montelukast sodium, the following events occurred with a frequency ≥2% and more
frequently than in pediatric patients who received placebo: fever, cough,
abdominal pain, diarrhea, headache, rhinorrhea, sinusitis, otitis, influenza,
rash, ear pain, gastroenteritis, eczema, urticaria, varicella, pneumonia,
dermatitis, and conjunctivitis.
Adults and Adolescents 15 Years of Age and Older
with Seasonal Allergic Rhinitis
Montelukast sodium has been evaluated for safety in 2199 adult and adolescent
patients 15 years of age and older in clinical trials. Montelukast sodium
administered once daily in the morning or in the evening had a safety profile
similar to that of placebo. In placebo-controlled clinical trials, the
following event was reported with montelukast sodium with a frequency ≥1%
and at an incidence greater than placebo: upper respiratory infection, 1.9% of
patients receiving montelukast sodium vs. 1.5% of patients receiving placebo.
In a 4-week, placebo-controlled clinical study, the safety profile was
consistent with that observed in 2-week studies. The incidence of somnolence
was similar to that of placebo in all studies.
Pediatric Patients 2 to 14 Years of Age with
Seasonal Allergic Rhinitis
Montelukast sodium have been evaluated in 280 pediatric patients 2 to 14
years of age in a 2-week, multicenter, double-blind, placebo-controlled,
parallel-group safety study. Montelukast sodium administered once daily in the
evening had a safety profile similar to that of placebo. In this study, the
following events occurred with a frequency ≥2% and at an incidence greater than
placebo: headache, otitis media, pharyngitis, and upper respiratory infection.
Adults and Adolescents 15 Years of Age and Older
with Perennial Allergic Rhinitis
Montelukast sodium has been evaluated for safety in 3357 adult and adolescent
patients 15 years of age and older with perennial allergic rhinitis of whom
1632 received montelukast sodium in two, 6-week, clinical studies. Montelukast
sodium administered once daily had a safety profile consistent with that
observed in patients with seasonal allergic rhinitis and similar to that of
placebo. In these two studies, the following events were reported with
montelukast sodium with a frequency ≥1% and at an incidence greater than
placebo: sinusitis, upper respiratory infection, sinus headache, cough,
epistaxis, and increased ALT. The incidence of somnolence was similar to that
of placebo.
Pediatric Patients 6 Months to 14 Years of Age with
Perennial Allergic Rhinitis
The safety in patients 2 to 14 years of age with perennial allergic rhinitis is
supported by the safety in patients 2 to 14 years of age with seasonal allergic
rhinitis.
Post-Marketing Experience
The following adverse reactions have been
identified during post-approval use of montelukast sodium. Because these
reactions are reported voluntarily from a population of uncertain size, it is
not always possible to reliably estimate their frequency or establish a causal
relationship to drug exposure.
Blood and lymphatic system disorders: increased bleeding tendency,
thrombocytopenia.
Immune system disorders: hypersensitivity reactions including anaphylaxis, hepatic
eosinophilic infiltration.
Psychiatric disorders: agitation including aggressive behavior or hostility,
anxiousness, depression, disorientation, disturbance in attention, dream
abnormalities, hallucinations, insomnia, irritability, memory impairment,
restlessness, somnambulism, suicidal thinking and behavior (including suicide),
tic, and tremor [see Warnings and Precautions (5.4)].
Nervous system disorders: drowsiness, paraesthesia/hypoesthesia, seizures.
Cardiac disorders: palpitations.
Respiratory, thoracic and mediastinal disorders: epistaxis, pulmonary
eosinophilia.
Gastrointestinal disorders: diarrhea, dyspepsia, nausea, pancreatitis,
vomiting.
Hepatobiliary disorders: Cases of cholestatic hepatitis, hepatocellular
liver-injury, and mixed-pattern liver injury have been reported in patients
treated with montelukast sodium. Most of these occurred in combination with
other confounding factors, such as use of other medications, or when
montelukast sodium was administered to patients who had underlying potential
for liver disease such as alcohol use or other forms of hepatitis.
Skin and subcutaneous tissue disorders: angioedema, bruising, erythema
multiforme, erythema nodosum, pruritus, Stevens-Johnson syndrome/toxic
epidermal necrolysis, urticaria.
Musculoskeletal and connective tissue disorders: arthralgia, myalgia including
muscle cramps.
Renal and urinary disorders: enuresis in children.
General disorders and administration site conditions: edema.
Patients with asthma on therapy with montelukast sodium may present with
systemic eosinophilia, sometimes presenting with clinical features of
vasculitis consistent with Churg-Strauss syndrome, a condition which is often
treated with systemic corticosteroid therapy. These events have been sometimes
associated with the reduction of oral corticosteroid therapy. Physicians should
be alert to eosinophilia, vasculitic rash, worsening pulmonary symptoms,
cardiac complications, and/or neuropathy presenting in their patients [see
Warnings and Precautions (5.5)].
Drug Interactions
No dose adjustment is needed when montelukast
sodium is co-administered with theophylline, prednisone, prednisolone, oral
contraceptives, terfenadine, digoxin, warfarin, gemfibrozil, itraconazole,
thyroid hormones, sedative hypnotics, non-steroidal anti-inflammatory agents,
benzodiazepines, decongestants, and Cytochrome P450 (CYP) enzyme inducers [see
Clinical Pharmacology (12.3)].
USE IN SPECIFIC POPULATIONS
Pregnancy
Pregnancy Category B: There are no adequate
and well-controlled studies in pregnant women. Because animal reproduction
studies are not always predictive of human response, montelukast sodium should
be used during pregnancy only if clearly needed.
Teratogenic Effect: No teratogenicity was observed in
rats and rabbits at doses approximately 100 and 110 times, respectively, the
maximum recommended daily oral dose in adults based on AUCs [see
Nonclinical Toxicology (13.2)].
During worldwide marketing experience, congenital limb defects have been rarely
reported in the offspring of women being treated with montelukast sodium during
pregnancy. Most of these women were also taking other asthma medications during
their pregnancy. A causal relationship between these events and montelukast
sodium has not been established.
Nursing Mothers
Studies in rats have shown that montelukast is
excreted in milk. It is not known if montelukast is excreted in human
milk.Because many drugs are excreted in human milk, caution should be exercised
when montelukast sodium is given to a nursing mother.
Pediatric Use
Safety and efficacy of montelukast sodium have been
established in adequate and well-controlled studies in pediatric patients with
asthma 6 to 14 years of age. Safety and efficacy profiles in this age group are
similar to those seen in adults [see
Adverse Reactions (6.1),
Clinical Pharmacology, Special Populations (12.3),
and Clinical Studies (14.1, 14.2)].
The efficacy of montelukast sodium for the treatment of seasonal allergic
rhinitis in pediatric patients 2 to 14 years of age and for the treatment of
perennial allergic rhinitis in pediatric patients 6 months to 14 years of age
is supported by extrapolation from the demonstrated efficacy in patients 15
years of age and older with allergic rhinitis as well as the assumption that
the disease course, pathophysiology and the drug’s effect are substantially
similar among these populations.
The safety of montelukast sodium 4-mg chewable tablets in pediatric
patients 2 to 5 years of age with asthma has been demonstrated by adequate and
well-controlled data [see Adverse Reactions (6.1)].Efficacy of montelukast
sodium in this age group is extrapolated from the demonstrated efficacy in
patients 6 years of age and older with asthma and is based on similar
pharmacokinetic data, as well as the assumption that the disease course,
pathophysiology and the drug’s effect are substantially similar among these
populations. Efficacy in this age group is supported by exploratory efficacy
assessments from a large, well-controlled safety study conducted in patients 2
to 5 years of age.
The safety of montelukast sodium sodium 4-mg and 5-mg chewable tablets in
pediatric patients aged 2 to 14 years with allergic rhinitis is supported by
data from studies conducted in pediatric patients aged 2 to 14 years with
asthma. A safety study in pediatric patients 2 to 14 years of age with seasonal
allergic rhinitis demonstrated a similar safety profile [see
Adverse Reactions (6.1)].
The safety and effectiveness in pediatric patients below the age of 12 months
with asthma, 6 months with perennial allergic rhinitis, and 6 years with
exercise-induced bronchoconstriction have not been established.
Growth Rate in Pediatric Patients
A 56-week, multi-center, double-blind, randomized, active- and
placebo-controlled parallel group study was conducted to assess the effect of
montelukast sodium on growth rate in 360 patients with mild asthma, aged 6 to 8
years. Treatment groups included montelukast sodium 5 mg once daily, placebo,
and beclomethasone dipropionate administered as 168 mcg twice daily with a
spacer device. For each subject, a growth rate was defined as the slope of a
linear regression line fit to the height measurements over 56 weeks. The
primary comparison was the difference in growth rates between montelukast
sodium and placebo groups. Growth rates, expressed as least-squares (LS) mean
(95% CI) in cm/year, for the montelukast sodium, placebo, and beclomethasone
treatment groups were 5.67 (5.46, 5.88), 5.64 (5.42, 5.86), and 4.86 (4.64,
5.08), respectively. The differences in growth rates, expressed as
least-squares (LS) mean (95% CI) in cm/year, for montelukast sodium minus
placebo, beclomethasone minus placebo, and montelukast sodium minus
beclomethasone treatment groups were 0.03 (-0.26, 0.31), -0.78 (-1.06, -0.49); and
0.81 (0.53, 1.09), respectively. Growth rate (expressed as mean change in
height over time) for each treatment group is shown in FIGURE 1.
Figure 1: Change in Height (cm) from Randomization
Visit by Scheduled Week (Treatment Group Mean ± Standard Error* of the Mean)
*The
standard errors of the treatment group means in change in height are too
small to be visible on the plot
Geriatric Use
Of the total number of subjects in clinical studies
of montelukast, 3.5% were 65 years of age and over, and 0.4% were 75 years of
age and over. No overall differences in safety or effectiveness were observed
between these subjects and younger subjects, and other reported clinical
experience has not identified differences in responses between the elderly and
younger patients, but greater sensitivity of some older individuals cannot be
ruled out. The pharmacokinetic profile and the oral bioavailability of a single
10-mg oral dose of montelukast are similar in elderly and younger adults. The
plasma half-life of montelukast is slightly longer in the elderly. No dosage
adjustment in the elderly is required.
Hepatic Insufficiency
No dosage adjustment is required in patients with
mild-to-moderate hepatic insufficiency [see
Clinical Pharmacology (12.3)].
Renal Insufficiency
No dosage adjustment is recommended in patients
with renal insufficiency [see Clinical Pharmacology (12.3)].
Overdosage
No specific information is available on the
treatment of overdosage with montelukast sodium. In chronic asthma studies,
montelukast has been administered at doses up to 200 mg/day to adult
patients for 22 weeks and, in short-term studies, up to 900 mg/day to patients
for approximately a week without clinically important adverse experiences. In
the event of overdose, it is reasonable to employ the usual supportive
measures; e.g., remove unabsorbed material from the gastrointestinal tract,
employ clinical monitoring, and institute supportive therapy, if required.
There have been reports of acute overdosage in post-marketing experience and
clinical studies with montelukast sodium. These include reports in adults and
children with a dose as high as 1000 mg. The clinical and laboratory findings
observed were consistent with the safety profile in adults and pediatric
patients. There were no adverse experiences in the majority of overdosage
reports. The most frequently occurring adverse experiences were consistent with
the safety profile of montelukast sodium and included abdominal pain,
somnolence, thirst, headache, vomiting and psychomotor hyperactivity.
It is not known whether montelukast is removed by peritoneal dialysis or
hemodialysis.
Montelukast Chewable Tablets
Description
Montelukast sodium, USP the active ingredient in
montelukast sodium chewable tablets, is a selective and orally active
leukotriene receptor antagonist that inhibits the cysteinyl leukotriene CysLT1 receptor.
Montelukast sodium, USP is described chemically as 1-[[[(1R)-1-[3-[(1E)-2-(7-Chloro-2-quinolinyl)
ethenyl] phenyl]-3-[2- (1-hydroxy-1-methylethyl) phenyl] propyl] thio] methyl]
cyclopropane acetic acid, sodium salt.
The empirical formula is C35H35ClNNaO3S, and its molecular weight is 608.17. The
structural formula is:
Montelukast sodium, USP is a hygroscopic, optically
active, white or almost white colored powder. Montelukast sodium, USP is freely
soluble in water and in methylene chloride, freely soluble to very soluble in
alcohol.
Each 4-mg and 5-mg chewable montelukast sodium tablets contain 4.16 and 5.2 mg
montelukast sodium, respectively, which are equivalent to 4-mg and 5-mg of
montelukast, respectively. Both chewable tablets contain the following inactive
ingredients: art cherry flavor, aspartame, croscarmellose sodium, ferric oxide
red, hydroxypropyl cellulose, magnesium stearate, mannitol and microcrystalline
cellulose.
Montelukast Chewable Tablets -
Clinical Pharmacology
Mechanism of Action
The cysteinyl leukotrienes (LTC4, LTD4, LTE4) are products of arachidonic acid
metabolism and are released from various cells, including mast cells and
eosinophils. These eicosanoids 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 airway edema, smooth
muscle contraction, and altered cellular activity associated with the
inflammatory process. 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.
Montelukast is an orally active compound that binds with high affinity and
selectivity to the CysLT1receptor (in preference to other pharmacologically
important airway receptors, such as the prostanoid, cholinergic, or
β-adrenergic receptor). Montelukast inhibits physiologic actions of LTD4 at the CysLT1receptor without any agonist
activity.
Pharmacodynamics
Montelukast causes inhibition of airway cysteinyl
leukotriene receptors as demonstrated by the ability to inhibit
bronchoconstriction due to inhaled LTD4 in asthmatics. Doses as low as 5 mg cause
substantial blockage of LTD4-induced bronchoconstriction. In a
placebo-controlled, crossover study (n=12), montelukast sodium inhibited early-
and late-phase bronchoconstriction due to antigen challenge by 75% and 57%,
respectively.
The effect of montelukast sodium on eosinophils in the peripheral blood was
examined in clinical trials. In patients with asthma aged 2 years and older who
received montelukast sodium, a decrease in mean peripheral blood eosinophil
counts ranging from 9% to 15% was noted, compared with placebo, over the
double-blind treatment periods. In patients with seasonal allergic rhinitis
aged 15 years and older who received montelukast sodium, a mean increase of
0.2% in peripheral blood eosinophil counts was noted, compared with a mean
increase of 12.5% in placebo-treated patients, over the double-blind treatment
periods; this reflects a mean difference of 12.3% in favor of montelukast
sodium. The relationship between these observations and the clinical benefits
of montelukast noted in the clinical trials is not known [see
Clinical Studies (14)].
Pharmacokinetics
Absorption
Montelukast is rapidly absorbed following oral administration. After
administration of the 10-mg film-coated tablet to fasted adults, the mean peak
montelukast plasma concentration (Cmax) is achieved in 3 to 4 hours (Tmax). The mean oral
bioavailability is 64%. The oral bioavailability and Cmax are not influenced by a
standard meal in the morning.
For the 5-mg chewable tablet, the mean Cmax is achieved in 2 to 2.5 hours
after administration to adults in the fasted state. The mean oral
bioavailability is 73% in the fasted state versus 63% when administered with a
standard meal in the morning.
For the 4-mg chewable tablet, the mean 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 safety and efficacy of montelukast sodium in patients with asthma were
demonstrated in clinical trials in which the 10-mg film-coated tablet and 5-mg
chewable tablet formulations were administered in the evening without regard to
the time of food ingestion. The safety of montelukast sodium in patients with
asthma was also demonstrated in clinical trials in which the 4-mg chewable
tablet formulations were administered in the evening without regard to the time
of food ingestion. The safety and efficacy of montelukast sodium in patients
with seasonal allergic rhinitis were demonstrated in clinical trials in which
the 10-mg film-coated tablet was administered in the morning or evening without
regard to the time of food ingestion.
The comparative pharmacokinetics of montelukast when administered as two 5-mg
chewable tablets versus one 10-mg film-coated tablet have not been evaluated.
Distribution
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
radiolabeled montelukast indicate minimal distribution across the blood-brain
barrier. In addition, concentrations of radiolabeled material at 24 hours
postdose were minimal in all other tissues.
Metabolism
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 CYP3A4, 2C8, and 2C9 are involved in the metabolism of
montelukast. At clinically relevant concentrations, 2C8 appears to play a major
role in the metabolism of montelukast.
Elimination
The plasma clearance of montelukast averages 45 mL/min in healthy adults.
Following an oral dose of radiolabeled montelukast, 86% of the radioactivity
was recovered in 5-day fecal collections and <0.2% was recovered in urine.
Coupled with estimates of montelukast oral bioavailability, this indicates that
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 are
nearly linear for oral doses up to 50 mg. During once-daily dosing with 10-mg
montelukast, there is little accumulation of the parent drug in plasma (14%).
Special Populations
Hepatic Insufficiency: Patients with mild-to-moderate
hepatic insufficiency and clinical evidence of cirrhosis had evidence of
decreased metabolism of montelukast resulting in 41 % (90% CI=7%, 85%) higher
mean montelukast AUC following a single 10-mg dose. The elimination of
montelukast was slightly prolonged compared with that in healthy subjects (mean
half-life, 7.4 hours). No dosage adjustment is required in patients with
mild-to-moderate hepatic insufficiency. The pharmacokinetics of montelukast
sodium in patients with more severe hepatic impairment or with hepatitis have
not been evaluated.
Renal Insufficiency: Since montelukast and its
metabolites are not excreted in the urine, the pharmacokinetics of montelukast
were not evaluated in patients with renal insufficiency. No dosage adjustment
is recommended in these patients.
Gender: The pharmacokinetics of montelukast are similar
in males and females.
Race: Pharmacokinetic differences due to race have not
been studied.
Adolescents and Pediatric Patients: Pharmacokinetic studies
evaluated the systemic exposure of the 4-mg chewable tablets in pediatric
patients 2 to 5 years of age, the 5-mg chewable tablets in pediatric patients 6
to 14 years of age, and the 10-mg film-coated tablets in young adults and
adolescents > 15 years of age.
The plasma concentration profile of montelukast following administration of the
10-mg film-coated tablet is similar in adolescents ≥15 years of age and young
adults. The 10-mg film-coated tablet is recommended for use in patients ≥15
years of age.
The mean systemic exposure of the 4-mg chewable tablet in pediatric patients 2
to 5 years of age and the 5-mg chewable tablets in pediatric patients 6 to 14
years of age is similar to the mean systemic exposure of the 10-mg film-coated
tablet in adults. The 5-mg chewable tablet should be used in pediatric patients
6 to 14 years of age and the 4-mg chewable tablet should be used in pediatric
patients 2 to 5 years of age.
In children 6 to 11 months of age, the systemic exposure to montelukast and the
variability of plasma montelukast concentrations were higher than those
observed in adults. Based on population analyses, the mean AUC (4296 ng•hr/mL
[range 1200 to 7153]) was 60% higher and the mean Cmax (667 ng/mL [range 201 to 1058])
was 89% higher than those observed in adults (mean AUC 2689 ng•hr/mL [range
1521 to 4595]) and mean Cmax (353 ng/mL [range 180 to 548]). The systemic
exposure in children 12 to 23 months of age was less variable, but was still
higher than that observed in adults. The mean AUC (3574 ng•hr/mL [range 2229 to
5408]) was 33% higher and the mean Cmax (562 ng/mL [range 296 to 814]) was 60% higher
than those observed in adults. Safety and tolerability of montelukast in a
single-dose pharmacokinetic study in 26 children 6 to 23 months of age were
similar to that of patients two years and above [see
Adverse Reactions (6.1)]. The 4-mg oral
granule formulation should be used for pediatric patients 12 to 23 months of
age for the treatment of asthma, or for pediatric patients 6 to 23 months of
age for the treatment of perennial allergic rhinitis. Since the 4-mg oral
granule formulation is bioequivalent to the 4-mg chewable tablet, it can also
be used as an alternative formulation to the 4-mg chewable tablet in pediatric
patients 2 to 5 years of age.
Drug-Drug Interactions
Theophylline, Prednisone, and Prednisolone: Montelukast sodium has
been administered with other therapies routinely used in the prophylaxis and
chronic treatment of asthma with no apparent increase in adverse reactions. In
drug-interaction studies, the recommended clinical dose of montelukast did not
have clinically important effects on the pharmacokinetics of the following
drugs: theophylline, prednisone, and prednisolone.
Montelukast at a dose of 10 mg once daily dosed to pharmacokinetic steady
state, did not cause clinically significant changes in the kinetics of a single
intravenous dose of theophylline [predominantly a cytochrome P450 (CYP) 1A2
substrate]. Montelukast at doses of ≥100 mg daily dosed to pharmacokinetic
steady state, did not cause any clinically significant change in plasma
profiles of prednisone or prednisolone following administration of either oral
prednisone or intravenous prednisolone.
Oral Contraceptives, Terfenadine, Digoxin, and
Warfarin: In
drug interaction studies, the recommended clinical dose of montelukast did not
have clinically important effects on the pharmacokinetics of the following
drugs: oral contraceptives (norethindrone 1 mg/ethinyl estradiol 35 mcg),
terfenadine, digoxin, and warfarin. Montelukast at doses of ≥100 mg daily dosed
to pharmacokinetic steady state did not significantly alter the plasma
concentrations of either component of an oral contraceptive containing norethindrone
1 mg/ethinyl estradiol 35 mcg. Montelukast at a dose of 10 mg once daily dosed
to pharmacokinetic steady state did not change the plasma concentration profile
of terfenadine (a substrate of CYP3A4) or fexofenadine, the carboxylated
metabolite, and did not prolong the QTc interval following co-administration
with terfenadine 60 mg twice daily; did not change the pharmacokinetic profile
or urinary excretion of immunoreactive digoxin; did not change the
pharmacokinetic profile of warfarin (primarily a substrate of CYP2C9, 3A4 and
1A2) or influence the effect of a single 30-mg oral dose of warfarin on
prothrombin time or the International Normalized Ratio (INR).
Thyroid Hormones, Sedative Hypnotics, Non-Steroidal
Anti-Inflammatory Agents, Benzodiazepines, and Decongestants: Although additional
specific interaction studies were not performed, montelukast sodium was used
concomitantly with a wide range of commonly prescribed drugs in clinical
studies without evidence of clinical adverse interactions. These medications
included thyroid hormones, sedative hypnotics, non-steroidal anti-inflammatory
agents, benzodiazepines, and decongestants.
Cytochrome P450 (CYP) Enzyme Inducers: Phenobarbital, which
induces hepatic metabolism, decreased the area under the plasma concentration
curve (AUC) of montelukast approximately 40% following a single 10-mg dose of
montelukast. No dosage adjustment for montelukast sodium is recommended. It is
reasonable to employ appropriate clinical monitoring when potent CYP enzyme inducers,
such as phenobarbital or rifampin, are co-administered with montelukast sodium
tablets.
Effect of Montelukast on Cytochrome P450 (CYP)
Enzymes: Montelukast
is a potent inhibitor of CYP2C8 in
vitro.
However, data from a clinical drug-drug interaction study involving montelukast
and rosiglitazone (a probe substrate representative of drugs primarily
metabolized by CYP2C8) in 12 healthy individuals demonstrated that the
pharmacokinetics of rosiglitazone are not altered when the drugs are
coadministered, indicating that montelukast does not inhibit CYP2C8 in
vivo.
Therefore, montelukast is not anticipated to alter the metabolism of drugs
metabolized by this enzyme (e.g., paclitaxel, rosiglitazone, and repaglinide).
Based on further in vitro results in human liver
microsomes, therapeutic plasma concentrations of montelukast do not inhibit CYP
3A4, 2C9, 1A2, 2A6, 2C19, or 2D6.
Cytochrome P450 (CYP) Enzyme Inhibitors:In vitro studies have shown
that montelukast is a substrate of CYP 2C8, 2C9, and 3A4. Co-administration of
montelukast with itraconazole, a strong CYP 3A4 inhibitor, resulted in no
significant increase in the systemic exposure of montelukast. Data from a
clinical drug-drug interaction study involving montelukast and gemfibrozil (an
inhibitor of both CYP 2C8 and 2C9) demonstrated that gemfibrozil, at a
therapeutic dose, increased the systemic exposure of montelukast by 4.4-fold.
Co-administration of itraconazole, gemfibrozil, and montelukast did not further
increase the systemic exposure of montelukast. Based on available clinical
experience, no dosage adjustment of montelukast is required upon
co-administration with gemfibrozil [see
Overdosage (10)].
Nonclinical Toxicology
Carcinogenesis & Mutagenesis
& Impairment Of Fertility
No evidence of tumorigenicity was seen in
carcinogenicity studies of either 2 years in Sprague-Dawley rats or 92 weeks in
mice at oral gavage doses up to 200 mg/kg/day or 100 mg/kg/day, respectively.
The estimated exposure in rats was approximately 120 and 75 times the AUC for
adults and children, respectively, at the maximum recommended daily oral dose.
The estimated exposure in mice was approximately 45 and 25 times the AUC for
adults and children, respectively, at the maximum recommended daily oral dose.
Montelukast demonstrated no evidence of mutagenic or clastogenic activity in
the following assays: the microbial mutagenesis assay, the V-79 mammalian cell
mutagenesis assay, the alkaline elution assay in rat hepatocytes, the
chromosomal aberration assay in Chinese hamster ovary cells, and in the in
vivomouse
bone marrow chromosomal aberration assay.
In fertility studies in female rats, montelukast produced reductions in fertility
and fecundity indices at an oral dose of 200 mg/kg (estimated exposure was
approximately 70 times the AUC for adults at the maximum recommended daily oral
dose). No effects on female fertility or fecundity were observed at an oral
dose of 100 mg/kg (estimated exposure was approximately 20 times the AUC for
adults at the maximum recommended daily oral dose). Montelukast had no effects
on fertility in male rats at oral doses up to 800 mg/kg (estimated exposure was
approximately 160 times the AUC for adults at the maximum recommended daily
oral dose).
Animal Pharmacology & OR
Toxicology
Reproductive Toxicology Studies
No teratogenicity was observed at oral doses up to 400 mg/kg/day and 300
mg/kg/day in rats and rabbits, respectively. These doses were approximately 100
and 110 times the maximum recommended daily oral dose in adults, respectively,
based on AUCs. Montelukast crosses the placenta following oral dosing in rats
and rabbits [see Pregnancy (8.1)].
Clinical Studies
Asthma
Adults and Adolescents 15 Years of
Age and Older with Asthma
Clinical trials in adults and adolescents 15 years of age and older
demonstrated there is no additional clinical benefit to montelukast doses above
10 mg once daily.
The efficacy of montelukast sodium for the chronic treatment of asthma in
adults and adolescents 15 years of age and older was demonstrated in two (U.S.and
Multinational) similarly designed, randomized, 12-week, double-blind,
placebo-controlled trials in 1576 patients (795 treated with montelukast
sodium, 530 treated with placebo, and 251 treated with active control). The
median age was 33 years (range 15 to 85); 56.8% were females and 43.2% were
males. The ethnic/racial distribution in these studies was 71.6% Caucasian,
17.7% Hispanic, 7.2% other origins and 3.5% Black. Patients had mild or moderate asthma and
were non-smokers who required approximately 5 puffs of inhaled β-agonist per
day on an "as-needed" basis. The patients had a mean baseline percent
of predicted forced expiratory volume in 1 second (FEV1) of 66% (approximate range, 40 to
90%). The co-primary endpoints in these trials were FEV1 and daytime asthma symptoms. In
both studies after 12 weeks, a random subset of patients receiving montelukast
sodium was switched to placebo for an additional 3 weeks of double-blind
treatment to evaluate for possible rebound effects.
The results of theU.S.trial on the primary endpoint, morning FEV1, expressed as mean percent change
from baseline averaged over the 12-week treatment period, are shown in FIGURE
2. Compared with placebo, treatment with one montelukast sodium 10-mg tablet
daily in the evening resulted in a statistically significant increase in FEV1 percent change from baseline
(13%-change in the group treated with montelukast sodium vs. 4.2%-change in the
placebo group, p<0.001); the change from baseline in FEV1 for montelukast sodium was 0.32
liters compared with 0.10 liters for placebo, corresponding to a between-group
difference of 0.22 liters (p<0.001, 95% CI 0.17 liters, 0.27 liters). The
results of the Multinational trial on FEV1 were similar.
Figure 2: FEV1 Mean
Percent Change from Baseline (U.S.Trial: Montelukast Sodium N=406; Placebo N=270) (ANOVA Model)
The effect of montelukast sodium on other primary
and secondary endpoints, represented by the Multinational study is shown in
TABLE 2. Results on these endpoints were similar in theUSstudy.
Table 2: Effect of Montelukast Sodium on Primary
and Secondary Endpoints in a Multinational Placebo-controlled Trial (ANOVA
Model)
|
|
Montelukast sodium
|
Placebo
|
|
Endpoint
|
N
|
Baseline
|
Mean change from Baseline
|
N
|
Baseline
|
Mean change from Baseline
|
|
Daytime Asthma symptoms(0
to 6 scale)
|
372
|
2.35
|
-0.49*
|
245
|
2.4
|
-0.26
|
|
β-agonist(puffs per day)
|
371
|
5.35
|
-1.65*
|
241
|
5.78
|
-0.42
|
|
AM PEFR(L/min)
|
372
|
339.57
|
25.03*
|
244
|
335.24
|
1.83
|
|
PM PEFR(L/min)
|
372
|
355.23
|
20.13*
|
244
|
354.02
|
-0.49
|
|
Nocturnal
Awakenings(#/week)
|
285
|
5.46
|
-2.03*
|
195
|
5.57
|
-0.78
|
Both studies evaluated the effect of montelukast
sodium on secondary outcomes, including asthma attack (utilization of
health-care resources such as an unscheduled visit to a doctor's office,
emergency room, or hospital; or treatment with oral, intravenous, or
intramuscular corticosteroid), and use of oral corticosteroids for asthma
rescue. In the Multinational study, significantly fewer patients (15.6% of
patients) on montelukast sodium experienced asthma attacks compared with
patients on placebo (27.3%,p < 0.001). In the US study,7.8% of patients on
montelukast sodium and 10.3% of patients on placebo experienced asthma attacks,
but the difference between the two treatment groups was not significant (p =
0.334). In the Multinational study, significantly fewer patients (14.8% of
patients) on montelukast sodium were prescribed oral corticosteroids for asthma
rescue compared with patients on placebo (25.7%, p < 0.001). In the US
study, 6.9% of patients on montelukast sodium and 9.9% of patients on placebo
were prescribed oral corticosteroids for asthma rescue, but the difference
between the two treatment groups was not significant (p = 0.196).
Onset of Action and Maintenance of Effects
In each placebo-controlled trial in adults, the treatment effect of montelukast
sodium, measured by daily diary card parameters, including symptom
scores, "as-needed" β-agonist use, and PEFR measurements, was
achieved after the first dose and was maintained throughout the dosing interval
(24 hours). No significant change in treatment effect was observed during
continuous
once-daily evening administration in non-placebo-controlled extension trials
for up to one year. Withdrawal of montelukast sodium in asthmatic patients
after 12 weeks of continuous use did not cause rebound worsening of asthma.
Pediatric Patients 6 to 14 Years of Age with Asthma
The efficacy of montelukast sodium in pediatric patients 6 to 14 years of age
was demonstrated in one 8-week, double-blind, placebo-controlled trial in 336
patients (201 treated with montelukast sodium and 135 treated with placebo) using an inhaled
β-agonist on an "as-needed" basis. The patients had a mean baseline
percent predicted FEV1 of 72% (approximate range, 45 to 90%) and a
mean daily inhaled β-agonist requirement of 3.4 puffs of albuterol.
Approximately 36% of the patients were on inhaled corticosteroids. The median age
was 11 years (range 6 to 15); 35.4% were females and 64.6% were males. The
ethnic/racial distribution in this study was 80.1% Caucasian, 12.8% Black, 4.5%
Hispanic, and 2.7% other origins.
Compared with placebo, treatment with one 5-mg montelukast sodium chewable
tablets daily resulted in a significant improvement in mean morning FEV1 percent change from baseline
(8.7% in the group treated with montelukast sodium vs. 4.2% change from
baseline in the placebo group, p<0.001). There was a significant
decrease in the mean percentage change in daily "as-needed" inhaled
β-agonist use (11.7% decrease from baseline in the group treated with
montelukast sodium vs. 8.2% increase from baseline in the placebo group,
p<0.05).
This effect represents a mean decrease from baseline of 0.56 and 0.23 puffs per
day for the montelukast and placebo groups, respectively. Subgroup analyses
indicated that younger pediatric patients aged 6 to 11 had efficacy results
comparable to those of the older pediatric patients aged 12 to 14.
Similar to the adult studies, no significant change in the treatment effect was
observed during continuous once-daily administration in one open-label
extension trial without a concurrent placebo group for up to 6 months.
Pediatric Patients 2 to 5 Years of Age with Asthma
The efficacy of montelukast sodium for the chronic treatment of asthma in
pediatric patients 2 to 5 years of age was explored in a 12-week,
placebo-controlled safety and tolerability study in 689 patients, 461 of whom
were treated with montelukast sodium. The median age was 4 years (range 2 to
6); 41.5% were females and 58.5% were males. The ethnic/racial distribution in
this study was 56.5% Caucasian, 20.9% Hispanic, 14.4% other origins, and 8.3% Black.
While the primary objective was to determine the safety and tolerability of
montelukast sodium in this age group, the study included exploratory efficacy
evaluations, including daytime and overnight asthma symptom scores, β-agonist
use, oral corticosteroid
rescue, and the physician's global evaluation. The findings of these
exploratory efficacy evaluations, along with pharmacokinetics and extrapolation
of efficacy data from older patients, support the overall conclusion that
montelukast sodium is efficacious in the maintenance treatment of asthma in
patients 2 to 5 years of age.
Effects in Patients on Concomitant Inhaled
Corticosteroids
Separate trials in adults evaluated the ability of montelukast sodium to add to
the clinical effect of inhaled corticosteroids and to allow inhaled
corticosteroid tapering when used concomitantly.
One randomized, placebo-controlled, parallel-group trial (n=226) enrolled
adults with stable asthma with a mean FEV1 of approximately 84% of
predicted who were previously maintained on various inhaled corticosteroids
(delivered by metered-dose aerosol or dry powder inhalers). The median age was
41.5 years (range 16 to 70); 52.2% were females and 47.8% were males. The
ethnic/racial distribution in this study was 92% Caucasian, 3.5% Black, 2.2%
Hispanic, and 2.2% Asian. The types of inhaled corticosteroids and their mean
baseline requirements included beclomethasone dipropionate (mean dose, 1203
mcg/day), triamcinolone acetonide (mean dose, 2004 mcg/day), flunisolide (mean dose,
1971 mcg/day), fluticasone propionate (mean dose, 1083 mcg/day), or budesonide
(mean dose, 1192 mcg/day). Some of these inhaled corticosteroids were
non-U.S.-approved formulations, and doses expressed may not be ex-actuator. The
pre-study inhaled corticosteroid requirements were reduced by approximately 37%
during a 5- to 7-week placebo run-in period designed to titrate patients toward
their lowest effective inhaled corticosteroid dose. Treatment with montelukast
sodium resulted in a further 47% reduction in mean inhaled corticosteroid dose
compared with a mean reduction of 30% in the placebo group over the 12-week
active treatment period (p≤0.05). It is not known whether the results of this
study can be generalized to patients with asthma who require higher doses of
inhaled corticosteroids or systemic corticosteroids.
In another randomized, placebo-controlled, parallel-group trial (n=642) in a
similar population of adult patients previously maintained, but not adequately
controlled, on inhaled corticosteroids (beclomethasone 336 mcg/day), the
addition of montelukast sodium to beclomethasone resulted in statistically
significant improvements in FEV1 compared with those patients who were
continued on beclomethasone alone or those patients who were withdrawn from
beclomethasone and treated with montelukast or placebo alone over the last 10
weeks of the 16-week, blinded treatment period. Patients who were randomized to
treatment arms containing beclomethasone had statistically significantly better
asthma control than those patients randomized to montelukast sodium alone or
placebo alone as indicated by FEV1, daytime asthma symptoms, PEFR, nocturnal
awakenings due to asthma, and "as-needed" β- agonist requirements.
In adult patients with asthma with documented aspirin sensitivity, nearly all of
whom were receiving concomitant inhaled and/or oral corticosteroids, a 4-week,
randomized, parallel-group trial (n=80) demonstrated that montelukast sodium,
compared with placebo, resulted in significant improvement in parameters of
asthma control. The magnitude of effect of montelukast sodium in
aspirin-sensitive patients was similar to the effect observed in the general
population of asthma patients studied. The effect of montelukast sodium on the
bronchoconstrictor response to aspirin or other non-steroidal anti-inflammatory
drugs in aspirin-sensitive asthmatic patients has not been evaluated [see
Warnings and Precautions (5.3)].
Exercise-Induced Bronchoconstriction
(EIB)
Exercise-Induced Bronchoconstriction
(Adults, Adolescents, and Pediatric Patients 6 years of age and older)
The efficacy of montelukast sodium, 10 mg, when given as a single dose 2 hours
before exercise for the prevention of EIB was investigated in three (U.S. and
Multinational), randomized, double-blind, placebo-controlled crossover studies
that included a total of 160 adult and adolescent patients 15 years of age and
older with EIB. Exercise challenge testing was conducted at 2 hours, 8.5 or 12
hours, and 24 hours following administration of a single dose of study drug
(montelukast sodium 10 mg or placebo). The primary endpoint was the mean
maximum percent fall in FEV1 following the 2 hours post-dose exercise challenge
in all three studies (Study A, Study B, and Study C). In Study A, a single dose
of montelukast sodium 10 mg demonstrated a statistically significant protective
benefit against EIB when taken 2 hours prior to exercise. Some patients were
protected from EIB at 8.5 and 24 hours after administration; however, some
patients were not. The results for the mean maximum percent fall at each
timepoint in Study A are shown in TABLE 3 and are representative of the results
from the other two studies.
Table 3: Mean Maximum Percent Fall in FEV1 Following
Exercise Challenge in Study A (N=47) ANOVA Model
|
Time of exercise challenge
following medication
administration
|
Mean Maximum percent fall in FEV1 *
|
Treatment difference
% for montelukast sodium versus Placebo (95% CI)*
|
|
Montelukast sodium
|
Placebo
|
|
2 hours
|
13
|
22
|
-9(-12,-5)
|
|
8.5 hours
|
12
|
17
|
-5(-9,-2)
|
|
24 hours
|
10
|
14
|
-4(-7,-1)
|
* Least squares-mean
The efficacy of montelukast sodium 5-mg chewable tablets, when given as a
single dose 2 hours before exercise for the prevention of EIB, was investigated
in one multinational, randomized, double-blind, placebo-controlled crossover
study that included a total of 64 pediatric patients 6 to 14 years of age with
EIB. Exercise challenge testing was conducted at 2 hours and 24 hours following
administration of a single dose of study drug (montelukast sodium 5 mg or
placebo). The primary endpoint was the mean maximum percent fall in FEV1 following the 2 hours post-dose
exercise challenge. A single dose of montelukast sodium 5 mg demonstrated a
statistically significant protective benefit against EIB when taken 2 hours
prior to exercise (TABLE 4). Similar results were shown at 24 hours post-dose
(a secondary endpoint). Some patients were protected from EIB at 24 hours after
administration; however, some patients were not. No timepoints were assessed
between 2 and 24 hours post-dose.
Table 4: Mean Maximum Percent Fall in FEV1 Following
Exercise Challenge in Pediatric Patients (N=64) ANOVA Model
|
Time of exercise challenge following
medication administration
|
Mean Maximum percent fall in FEV1*
|
Treatment difference % formontelukast sodium
versus Placebo (95% CI)*
|
|
|
Montelukast sodium
|
Placebo
|
|
|
2 hours
|
15
|
20
|
-5 (-9, -1)
|
|
24 hours
|
13
|
17
|
-4 (-7, -1)
|
*Least squares-mean
The efficacy of montelukast sodium for prevention of EIB in patients below 6
years of age has not been established.
Daily administration of montelukast sodium for the chronic treatment of asthma
has not been established to prevent acute episodes of EIB.
In a 12-week, randomized, double-blind, parallel group study of 110 adult and
adolescent asthmatics 15 years of age and older, with a mean baseline FEV1 percent of predicted of 83% and
with documented exercise-induced exacerbation of asthma, treatment with
montelukast sodium, 10 mg, once daily in the evening, resulted in a
statistically significant reduction in mean maximal percent fall in FEV1 and mean time to recovery to
within 5% of the pre-exercise FEV1. Exercise challenge was conducted at the end of
the dosing interval (i.e., 20 to 24 hours after the preceding dose). This
effect was maintained throughout the 12-week treatment period indicating that
tolerance did not occur. Montelukast sodium did not, however, prevent
clinically significant deterioration in maximal percent fall in FEV1 after exercise (i.e., ≥20%
decrease from pre-exercise baseline) in 52% of patients studied. In a separate
crossover study in adults, a similar effect was observed after two once-daily
10-mg doses of montelukast sodium.
In pediatric patients 6 to 14 years of age, using the 5-mg chewable tablet, a
2-day crossover study demonstrated effects similar to those observed in adults when
exercise challenge was conducted at the end of the dosing interval (i.e., 20 to
24 hours after the preceding dose).
Allergic Rhinitis (Seasonal and
Perennial)
Seasonal Allergic Rhinitis
The efficacy of montelukast sodium tablets for the treatment of seasonal
allergic rhinitis was investigated in 5 similarly designed, randomized,
double-blind, parallel-group, placebo- and active-controlled (loratadine)
trials conducted in North America. The 5 trials enrolled a total of 5029
patients, of whom 1799 were treated with montelukast sodium tablets. Patients
were 15 to 82 years of age with a history of seasonal allergic rhinitis, a
positive skin test to at least one relevant seasonal allergen, and active
symptoms of seasonal allergic rhinitis at study entry.
The period of randomized treatment was 2 weeks in 4 trials and 4 weeks in one
trial. The primary outcome variable was mean change from baseline in daytime
nasal symptoms score (the average of individual scores of nasal congestion,
rhinorrhea, nasal itching, sneezing) as assessed by patients on a 0 to 3
categorical scale.
Four of the five trials showed a significant reduction in daytime nasal
symptoms scores with montelukast sodium 10-mg tablets compared with placebo.
The results of one trial are shown below. The median age in this trial was 35
years (range 15 to 81); 65.4% were females and 34.6% were males. The
ethnic/racial distribution in this study was 83.1% Caucasian, 6.4% other
origins, 5.8% Black, and 4.8% Hispanic. The mean changes from baseline in
daytime nasal symptoms score in the treatment groups that received montelukast
sodium tablets, loratadine, and placebo are shown in TABLE 5. The remaining
three trials that demonstrated efficacy showed similar results.
Table 5: Effects of Montelukast Sodium on Daytime
Nasal Symptoms Score* in a Placebo- and Active-controlled Trial in Patients
with Seasonal Allergic Rhinitis (ANCOVA Model)
|
Treatment
Group (N)
|
Baseline Mean
Score
|
Mean Change
from Baseline
|
Difference
Between Treatment
and Placebo (95% CI)
Least-Squares
Mean
|
|
Montelukast Sodium 10 mg
(344)
|
2.09
|
-0.39
|
-0.13† (-0.21,-0.06)
|
|
Placebo (351)
|
2.10
|
-0.26
|
N.A.
|
|
Active Control‡
(Loratadine 10 mg) (599)
|
2.06
|
-0.46
|
-0.24 † (-0.31,-0.17)
|
* Average of individual scores of nasal congestion,
rhinorrhea, nasal itching, sneezing as assessed by patients on a 0 to 3
categorical scale.
† Statistically different from placebo (p≤0.001).
‡ The study was not designed for statistical comparison between
montelukast sodium and the active control (loratadine).
Perennial Allergic Rhinitis
The efficacy of montelukast sodium tablets for the treatment of perennial
allergic rhinitis was investigated in 2 randomized, double-blind,
placebo-controlled studies conducted in North America andEurope.
The two studies enrolled a total of 3357 patients, of whom 1632 received
montelukast sodium 10-mg tablets. Patients 15 to 82 years of age with perennial
allergic rhinitis as confirmed by history and a positive skin test to at least
one relevant perennial allergen (dust mites, animal dander, and/or mold
spores), who had active symptoms at the time of study entry, were enrolled.
In the study in which efficacy was demonstrated, the median age was 35 years
(range 15 to 81); 64.1% were females and 35.9% were males. The ethnic/racial
distribution in this study was 83.2% Caucasian, 8.1% Black, 5.4% Hispanic, 2.3%
Asian, and 1% other origins. Montelukast sodium 10-mg tablets once daily
was shown to significantly reduce symptoms of perennial allergic rhinitis over
a 6-week treatment period (TABLE 6); in this study the primary outcome variable
was mean change from baseline in daytime nasal symptoms score (the average of
individual scores of nasal congestion, rhinorrhea, and sneezing).
Table 6: Effects of Montelukast Sodium on Daytime
Nasal Symptoms Score* in a Placebo-controlled Trial in Patients with Perennial
Allergic Rhinitis (ANCOVA Model)
|
Treatment Group (N)
|
Baseline mean Score
|
Mean Change
from Baseline
|
Difference between Treatment
and Placebo (95% CI)
Least-Squares Mean
|
|
Montelukast Sodium 10 mg
(1000)
|
2.09
|
-0.42
|
-0.08† (-0.12, -0.04)
|
|
Placebo
(980)
|
2.10
|
-0.35
|
N.A.
|
* Average of individual scores of nasal
congestion, rhinorrhea, sneezing as assessed by patients on a 0 to 3
categorical scale.
† Statistically different from placebo
(p≤0.001).
The other 6-week study evaluated montelukast sodium 10 mg (n=626), placebo
(n=609), and an active-control (cetirizine 10 mg; n=120). The primary analysis
compared the mean change from baseline in daytime nasal symptoms score for montelukast
sodium vs. placebo over the first 4 weeks of treatment; the study was not
designed for statistical comparison between montelukast sodium and the
active-control. The primary outcome variable included nasal itching in addition
to nasal congestion, rhinorrhea, and sneezing. The estimated difference between
montelukast sodium and placebo was -0.04 with a 95% CI of (-0.09, 0.01). The
estimated difference between the active-control and placebo was -0.10 with a
95% CI of (-0.19, -0.01).
How Supplied/Storage and Handling
Montelukast Sodium 4-mg (equivalent to 4-mg
montelukast) Chewable Tablets are light pink colored, speckled, oval, biconvex
shaped, chewable tablets debossed with 'I' on one side and '112' on the other
side. They are supplied as follows:
Bottles of 30
tablets
NDC 31722-727-30
Bottles of 90
tablets
NDC 31722-727-90
Bottles of 100
tablets
NDC 31722-727-01
Bottles of 1000
tablets
NDC 31722-727-10
Blister card of 10 Unit-dose
tablets
NDC 31722-727-31
Blister pack of 100 (10 x 10) Unit-dose
tablets NDC 31722-727-32
Montelukast Sodium 5-mg (equivalent to 5-mg montelukast) Chewable Tablets are
light pink colored, speckled, round, biconvex shaped, chewable tablets debossed
with 'I' on one side and '113' on the other side.
Bottles of 30
tablets
NDC 31722-728-30
Bottles of 90
tablets NDC
31722-728-90
Bottles of 100
tablets
NDC 31722-728-01
Bottles of 1000 tablets
NDC 31722-728-10
Blister card of 10 Unit-dose
tablets
NDC 31722-728-31
Blister pack of 100 (10 x 10) Unit-dose
tablets NDC
31722-728-32
Storage
Store at 20° to 25° C (68° to 77° F) [see USP
Controlled Room Temperature]. Protect from moisture and light. Store in
original container. When product container is subdivided, repackage into a
well-closed, light-resistance container.
Patient Counseling Information
See FDA-approved patient labeling
(Patient Information).
Information for Patients
•Patients should be advised to take montelukast sodium chewable tablets daily
as prescribed, even when they are asymptomatic, as well as during periods of
worsening asthma, and to contact their physicians if their asthma is not well
controlled.
•Patients should be advised that oral montelukast sodium chewable tablets are
not for the treatment of acute asthma attacks. They should have appropriate
short-acting inhaled β-agonist medication available to treat asthma
exacerbations. Patients who have exacerbations of asthma after exercise should
be instructed to have available for rescue a short-acting inhaled β-agonist.
Daily administration of montelukast sodium tablets for the chronic treatment of asthma has not been
established to prevent acute episodes of EIB.
•Patients should be advised that, while using montelukast sodium chewable
tablets, medical attention should be sought if short-acting inhaled
bronchodilators are needed more often than usual, or if more than the maximum
number of inhalations of short-acting bronchodilator treatment prescribed for a
24-hour period are needed.
•Patients receiving montelukast sodium chewable tablets should be instructed
not to decrease the dose or stop taking any other anti-asthma medications
unless instructed by a physician.
•Patients should be instructed to notify their physician if neuropsychiatric
events occur while using montelukast sodium chewable tablets.
•Patients with known aspirin sensitivity should be advised to continue
avoidance of aspirin or non-steroidal anti-inflammatory agents while taking
montelukast sodium chewable tablets.
•Phenylketonuric patients should be informed that the 4-mg and 5-mg chewable
tablets contain phenylalanine (a component of aspartame).
Manufactured for:
Manufactured for:
Camber Pharmaceuticals, Inc.
Piscataway,NJ08854.
By: HETEROTM
Hetero Labs Limited Unit-V, Polepally,
Jadcherla,
Mahaboob Nagar-509 301,India.
Barcode
Revised: 05/2017
