TEMOST

Montelukast was first approved for clinical use by the US FDA in as Merck's brand name Singulair.

The medication is a member of the leukotriene receptor antagonist (LTRA) category of drugs. 3, 4, 5, 6, 7, 8, 9 Although capable of demonstrating effectiveness, the use of such LTRAs like montelukast is typically in addition to or complementary with the use of inhaled corticosteroids or other agents in asthma step therapy.

Regardless, in 2008-2009, there were FDA-led investigations into the possibility of montelukast to elicit neuropsychiatric effects like agitation, hallucinations, suicidal behaviour, and others in individuals who used the medication.

And although these kinds of effects are currently included in the official prescribing information for montelukast, 3, 4, 5, 6, 7, 8, 9 the drug still sees extensive use worldwide via millions of prescriptions annually and has since become available as a generic and as a brand name product.

Montelukast is indicated for: (a) the prophylaxis and chronic treatment of asthma in adults and pediatric patients who are 12 months of age and older 3, although other regional health authorities specifically note this indication for adults and adolescents who are 15 years and older 4, 5 and also include indications for preventing day and night-time symptoms, and the treatment of acetylsalicylic acid-sensitive asthma 4; (b) the prevention of exercise-induced bronchoconstriction (EIB) in patients who are 6 years of age and older 3, although other regional health authorities specifically note this indication for adults and adolescents who are 15 years and older 4, 5; and (c) the relief of symptoms of seasonal allergic rhinitis in patients 2 years of age and older and perennial allergic rhinitis in patients 6 months of age and older 3, although other regional health authorities specifically note the relief of seasonal allergic rhinitis symptoms for adults and adolescents who are 15 years and older 4, 5.

Furthermore, some formulations like chewable montelukast tablets may also be specifically indicated by particular regulatory bodies for the prophylaxis and chronic treatment of asthma, including the prevention of day and night-time symptoms, the treatment of acetylsalicylic acid based asthma, and the prevention of exercise-induced bronchoconstriction in adult and pediatric patients aged and older 8, between the ages and 5 7, or between the ages of and 14 years.

Moreover, when employed for such indications montelukast is considered effective as monotherapy or when combined with other medications indicated for the maintenance treatment of chronic asthma. 4, 8 For instance, montelukast and inhaled corticosteroids can be used concomitantly to demonstrate additive effects to control asthma or to decrease the necessary inhaled corticosteroid dose while still maintaining clinical stability. 4, 8 Additionally, in patients who continue to experience asthma symptoms, montelukast can also be combined with an'as required'short-acting beta-agonist, an inhaled corticosteroid, or inhaled corticosteroid paired with a long-acting beta-agonist. 4,

Montelukast is a leukotriene receptor antagonist that demonstrates a marked affinity and selectivity to the cysteinyl leukotriene receptor type-1 in preference to many other crucial airway receptors like the prostanoid, cholinergic, or beta-adrenergic receptors. 3, 4, 5, 6, 7, 8, 9 As a consequence, the agent can elicit substantial blockage of LTD4 leukotriene-mediated bronchoconstriction with doses as low as 5 mg. 3, 4, 5, 6, 7, 8, 9 Moreover, a placebo-controlled, crossover study (n=12) demonstrated that montelukast is capable of inhibiting early and late phase bronchoconstriction caused by antigen challenge by 75% and 57% respectively. 3, 4, 5, 6, 7, 8, 9 In particular, it has been documented that montelukast can cause bronchodilation as soon as within 2 hours of oral administration. 3, 4, 5, 6, 7, 8, 9 This action can also be additive to the bronchodilation caused by the concomitant use of a beta agonist. 3, 4, 5, 6, 7, 8, 9 Nevertheless, clinical investigations performed with adults 15 years of age and older revealed that no additional clinical benefit is obtained when doses of montelukast greater than 10 mg a day are used. 3, 4, 5, 6, 7, 8, 9 Additionally, in clinical trials with adults and pediatric asthmatic patients aged 6-14 years, it was also determined that montelukast can reduce mean peripheral blood eosinophils by about 13% to 15% from baseline in comparison to placebo during double-blind treatment periods. 3, 4, 5, 6, 7, 8, 9 At the same time, in patients aged 15 years and older who were experiencing seasonal allergic rhinitis, the use of montelukast caused a median reduction of 13% in peripheral blood eosinophil counts when compared to placebo as well. 3, 4, 5, 6, 7, 8, 9.

It has been observed that montelukast is quickly absorbed following administration by the oral route. 3, 4, 5, 6, 7, 8, 9 The oral bioavailability documented for the drug is 64%. 3, 4, 5, 6, 7, 8, 9 Furthermore, it seems that having a regular meal in the morning or even a high fat snack in the evening does not affect the absorption of montelukast. 3, 4, 5, 6, 7, 8, 9.

The steady-state volume of distribution recorded for montelukast is an average between 8-11 litres. 3, 4, 5, 7, 8, 9.

It has been determined that montelukast is highly metabolized and typically so by the cytochrome P450 3A4, 2C8, and 2C9 isoenzymes. 3, 4, 5, 6, 7, 8, 9 In particular, it seems that the CYP2C8 enzymes play a significant role in the metabolism of the drug. 3, 4, 5, 6, 7, 8, 9 Nevertheless, at therapeutic doses, the plasma concentrations of montelukast metabolites are undetectable at steady state in adults and pediatric patients. 3, 4, 5, 6, 7, 8, 9 Hover over products below to view reaction partners Montelukast Montelukast metabolite M1 Montelukast metabolite M2a Montelukast metabolite M2b Montelukast metabolite M5a Montelukast metabolite M5b Montelukast metabolite M6a Montelukast metabolite M6b montelukast sulfoxide 21-Hydroxymontelukast 21(S)-Hydroxy Montelukast Montelukast 1, 2-Diol.

It has been reported that montelukast and its metabolites are almost exclusively excreted in the bile and into the feces. 3, 4, 5, 6, 7, 8, 9.

Studies have demonstrated that the mean plasma half-life of montelukast varies from 2.7-5.5 hours when observed in healthy young adults. 3, 4, 5, 7, 8, 9.

The plasma clearance documented for montelukast is an average of 45 mL/min when observed in healthy adults. 3, 4, 5, 7, 8, 9.

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The adverse effects associated with overdosage of montelukast include abdominal pain, somnolence, thirst, headache, vomiting, psychomotor hyperactivity, and less frequently, convulsion. 3, 4, 5, 6, 7, 8, 9 The oral LD50 value determined for mice and rats is >5000 mg/kg. 3, 4, 5, 6, 7, 8, 9 Montelukast has not been studied in pregnant women. 3, 4, 5, 6, 7, 8, 9 Consequently, it should be used during pregnancy only if clearly needed. 3, 4, 5, 6, 7, 8, 9 Additionally, as it is unknown whether montelukast is excreted into human breast milk, there is also caution regarding the use of the medication in nursing mothers. 3, 4, 5, 6, 7, 8, 9 The plasma half-life of montelukast is somewhat prolonged in elderly patients, although no dosage adjustment is generally necessary. 3, 4, 5, 6, 7, 8, 9.

• Hypersensitivity to any component of this product.

• Hypersensitivity to any component of this product.

• Asthma: Once daily in the evening for patients 2 years and older.

• Acute prevention of EIB: One tablet at least 2 hours before exercise for patients 6 years of age and older.

• Seasonal allergic rhinitis: Once daily for patients 2 years and older.

• Perennial allergic rhinitis: Once daily for patients 2 years and older.

• 15 years and older: one 10-mg tablet.

• 6 to 14 years: one 5-mg chewable tablet.

• 2 to 5 years: one 4-mg chewable tablet.

Patients with both asthma and allergic rhinitis should take only one dose daily in the evening. 2.1 Asthma Montelukast sodium 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 to 14 years of age: one 5-mg chewable tablet.

For pediatric patients 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. who miss a dose should take the next dose at their regular time and should not take 2 doses at the same time.

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.

Montelukast sodium should be taken once daily in the evening.

Safety and effectiveness in pediatric patients less than 12 months of age with asthma have not been established.

Patients who miss a dose should take the next dose at their regular time and should not take 2 doses at the same time.

Efficacy has been demonstrated for asthma when montelukast was administered in the evening without regard to time of food ingestion. 2.2 Exercise-lnduced Bronchoconstriction (EIB) For prevention of EIB, a single dose of montelukast sodium should be taken at least 2 hours before exercise.

An additional dose of montelukast sodium should not be taken within 24 hours of a previous dose.

Patients already taking montelukast sodium 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 for the chronic treatment of asthma has not been established to prevent acute episodes of EIB. 2.3 Allergic Rhinitis For allergic rhinitis, montelukast sodium 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.

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 allergic rhinitis, montelukast sodium should be taken once daily.

Safety and effectiveness in pediatric patients younger than 6 months of age with perennial allergic rhinitis have not been established. who miss a dose should take the next dose at their regular time and should not take 2 doses at the same time.

Safety and effectiveness in pediatric patients younger than 6 months of age with perennial allergic rhinitis have not been established.

Patients who miss a dose should take the next dose at their regular time and should not take 2 doses at the same time. 2.4 Asthma and Allergic Rhinitis Patients with both asthma and allergic rhinitis should take only one montelukast sodium dose daily in the evening.

Patients with both asthma and allergic rhinitis should take only one montelukast sodium dose daily in the evening. who miss a dose should take the next dose at their regular time and should not take 2 doses at the same time.

50090-7920 NDC: 50090-7920-0 30 TABLET, CHEWABLE in a BOTTLE NDC: 50090-7920-1 90 TABLET, CHEWABLE in a BOTTLE.

Available data from published prospective and retrospective cohort studies over decades with montelukast use in pregnant women have not established a drug-associated risk of major birth defects.

In animal reproduction studies, no adverse developmental effects were observed with oral administration of montelukast to pregnant rats and rabbits during organogenesis at doses approximately and 110 times, respectively, the maximum recommended human daily oral dose (MRHDOD) based on AUCs.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

In the

U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is to 4% and to 20%, respectively.

Disease-associated maternal and/or embryo/fetal risk Poorly or moderately controlled asthma in pregnancy increases the maternal risk of perinatal adverse outcomes such as preeclampsia and infant prematurity, low birth weight, and small for gestational age.

Published data from prospective and retrospective cohort studies have not identified an association with montelukast sodium use during pregnancy and major birth defects.

Available studies have methodologic limitations, including small sample size, in some cases retrospective data collection, and inconsistent comparator groups.

In embryo-fetal development studies, montelukast administered to pregnant rats and rabbits during organogenesis (gestation days to 17 in rats and to 18 in rabbits) did not cause any adverse developmental effects at maternal oral doses up to and 300 mg/kg/day in rats and rabbits, respectively (approximately and 110 times the AUC in humans at the MRHDOD, respectively).

Safety and efficacy of montelukast sodium have been established in adequate and well-controlled studies in pediatric patients with asthma to 14 years of age.

Safety and efficacy profiles in this are similar to those seen in adults.

The efficacy of montelukast sodium for the treatment of seasonal allergic rhinitis in pediatric patients to 14 years of age and for the treatment of perennial allergic rhinitis in pediatric patients 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 to 5 years of age with asthma has been demonstrated by adequate and well-controlled data.

Efficacy of montelukast sodium in this 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 is supported by exploratory efficacy assessments from a large, well-controlled safety study conducted in patients to 5 years of age.

The safety of montelukast sodium 4-mg and 5-mg chewable tablets in pediatric patients aged to 14 years with allergic rhinitis is supported by data from studies conducted in pediatric patients aged to 14 years with asthma.

A safety study in pediatric patients to 14 years of age with seasonal allergic rhinitis demonstrated a similar safety profile.

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.

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 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, 5.64, and 4.86, 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, 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 Figure1.

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.