Singulair Information
Singulair (Montelukast sodium) Description
Montelukast sodium, the active ingredient in Singulair (Montelukast sodium) , is a selective and orally active leukotriene receptor antagonist that inhibits the cysteinyl leukotriene CysLT receptor.
Montelukast sodium is described chemically as [-()]-1-[[[1-[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl]thio]methyl]cyclopropaneacetic acid, monosodium salt.
The empirical formula is CHClNNaOS, and its molecular weight is 608.18. The structural formula is:
Montelukast sodium is a hygroscopic, optically active, white to off-white powder. Montelukast sodium is freely soluble in ethanol, methanol, and water and practically insoluble in acetonitrile.
Each 10-mg film-coated Singulair (Montelukast sodium) tablet contains 10.4 mg montelukast sodium, which is equivalent to 10 mg 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.
Each 4-mg and 5-mg chewable Singulair (Montelukast sodium) tablet contains 4.2 and 5.2 mg montelukast sodium, respectively, which are equivalent to 4 and 5 mg of montelukast, respectively. Both chewable tablets contain the following inactive ingredients: mannitol, microcrystalline cellulose, hydroxypropyl cellulose, red ferric oxide, croscarmellose sodium, cherry flavor, aspartame, and magnesium stearate.
Each packet of Singulair (Montelukast sodium) 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.
Singulair (Montelukast sodium) Clinical Pharmacology
The cysteinyl leukotrienes (LTC, LTD, LTE) 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 (CysLT) 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. Intranasal challenge with CysLTs has been shown to increase nasal airway resistance and symptoms of nasal obstruction. Singulair (Montelukast sodium) has not been assessed in intranasal challenge studies. The clinical relevance of intranasal challenge studies is unknown.
Montelukast is an orally active compound that binds with high affinity and selectivity to the CysLT receptor (in preference to other pharmacologically important airway receptors, such as the prostanoid, cholinergic, or β-adrenergic receptor). Montelukast inhibits physiologic actions of LTD at the CysLT receptor without any agonist activity.
Montelukast at a dose of 10 mg once daily dosed to pharmacokinetic steady state:
Montelukast at doses of ≥100 mg daily dosed to pharmacokinetic steady state:
Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for Singulair (Montelukast sodium) is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with Singulair (Montelukast sodium) .
Montelukast is a potent inhibitor of P450 2C8 . 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 . Therefore, montelukast is not anticipated to alter the metabolism of drugs metabolized by this enzyme (e.g., paclitaxel, rosiglitazone, and repaglinide.)
Montelukast causes inhibition of airway cysteinyl leukotriene receptors as demonstrated by the ability to inhibit bronchoconstriction due to inhaled LTD in asthmatics. Doses as low as 5 mg cause substantial blockage of LTD-induced bronchoconstriction. In a placebo-controlled, crossover study (n=12), Singulair (Montelukast sodium) inhibited early- and late-phase bronchoconstriction due to antigen challenge by 75% and 57%, respectively.
The effect of Singulair (Montelukast sodium) on eosinophils in the peripheral blood was examined in clinical trials. In patients with asthma aged 2 years and older who received Singulair (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 Singulair (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 Singulair (Montelukast sodium) . The relationship between these observations and the clinical benefits of montelukast noted in the clinical trials is not known (see ).
The efficacy of Singulair (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 Singulair (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 0-3 categorical scale.
Four of the five trials showed a significant reduction in daytime nasal symptoms scores with Singulair (Montelukast sodium) 10-mg tablets compared with placebo. The efficacy results of one trial are shown below; the remaining three trials that demonstrated efficacy showed similar results. The mean changes from baseline in daytime nasal symptoms score in the treatment groups that received Singulair (Montelukast sodium) tablets, loratadine and placebo are shown in TABLE 4.
The efficacy of Singulair (Montelukast sodium) tablets for the treatment of perennial allergic rhinitis was investigated in 2 randomized, double-blind, placebo-controlled studies conducted in North America and Europe. The two studies enrolled a total of 3357 patients, of whom 1632 received Singulair (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, Singulair (Montelukast sodium) 10-mg tablets once daily was shown to significantly reduce symptoms of perennial allergic rhinitis over a 6-week treatment period (TABLE 5); 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).
The other 6-week study evaluated Singulair (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 Singulair (Montelukast sodium) vs. placebo over the first 4 weeks of treatment; the study was not designed for statistical comparison between Singulair (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 Singulair (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).
Singulair (Montelukast sodium) Indications And Usage
Singulair (Montelukast sodium) is indicated for the prophylaxis and chronic treatment of asthma in adults and pediatric patients 12 months of age and older.
Singulair (Montelukast sodium) is indicated for prevention of exercise-induced bronchoconstriction in patients 15 years of age and older.
Singulair (Montelukast sodium) is indicated for the relief of 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).
Singulair (Montelukast sodium) Contraindications
Hypersensitivity to any component of this product.
Singulair (Montelukast sodium) Precautions
Singulair (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 Singulair (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.
While the dose of inhaled corticosteroid may be reduced gradually under medical supervision, Singulair (Montelukast sodium) should not be abruptly substituted for inhaled or oral corticosteroids.
Patients with known aspirin sensitivity should continue avoidance of aspirin or non-steroidal anti-inflammatory agents while taking Singulair (Montelukast sodium) . Although Singulair (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 ).
Singulair (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, prednisolone, oral contraceptives (norethindrone 1 mg/ethinyl estradiol 35 mcg), terfenadine, digoxin, and warfarin.
Although additional specific interaction studies were not performed, Singulair (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.
Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for Singulair (Montelukast sodium) is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with Singulair (Montelukast sodium) .
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 area under the plasma concentration versus time curve (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 mouse 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).
Safety and efficacy of Singulair (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 and .)
The efficacy of Singulair (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 Singulair (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 ). Efficacy of Singulair (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 Singulair (Montelukast sodium) 4-mg oral granules in pediatric patients 12 to 23 months of age with asthma has been demonstrated in an analysis of 172 pediatric patients, 124 of whom were treated with Singulair (Montelukast sodium) , in a 6-week, double-blind, placebo-controlled study (see ). Efficacy of Singulair (Montelukast sodium) in this age group is extrapolated from the demonstrated efficacy in patients 6 years of age and older with asthma based on similar mean systemic exposure (AUC), and that the disease course, pathophysiology and the drug’s effect are substantially similar among these populations, supported by efficacy data from a safety trial in which efficacy was an exploratory assessment.
The safety of Singulair (Montelukast 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 ). The safety of Singulair (Montelukast sodium) 4-mg oral granules in pediatric patients as young as 6 months of age with perennial allergic rhinitis is supported by extrapolation from safety data obtained from studies conducted in pediatric patients 6 months to 23 months of age with asthma and from pharmacokinetic data comparing systemic exposures in patients 6 months to 23 months of age to systemic exposures in adults.
The safety and effectiveness in pediatric patients below the age of 12 months with asthma and 6 months with perennial allergic rhinitis have not been established.
Singulair (Montelukast sodium) Adverse Reactions
Singulair (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 Singulair (Montelukast sodium) occurred in greater than or equal to 1% of patients and at an incidence greater than that in patients treated with placebo, regardless of causality assessment:
The frequency of less common adverse events was comparable between Singulair (Montelukast sodium) and placebo.
The safety profile of Singulair (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 Singulair (Montelukast sodium) .
Cumulatively, 569 patients were treated with Singulair (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.
Singulair (Montelukast sodium) has been evaluated for safety in 476 pediatric patients 6 to 14 years of age. Cumulatively, 289 pediatric patients were treated with Singulair (Montelukast sodium) for at least 6 months, and 241 for one year or longer in clinical trials. The safety profile of Singulair (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 Singulair (Montelukast sodium) , the following events occurred with a frequency ≥2% and more frequently than in pediatric patients who received placebo, regardless of causality assessment: pharyngitis, influenza, fever, sinusitis, nausea, diarrhea, dyspepsia, otitis, viral infection, and laryngitis. The frequency of less common adverse events was comparable between Singulair (Montelukast sodium) and placebo. With prolonged treatment, the adverse experience profile did not significantly change.
In studies evaluating growth rate, the safety profile in these pediatric patients was consistent with the safety profile previously described for Singulair (Montelukast sodium) . In a 56-week, double-blind study evaluating growth rate in pediatric patients 6 to 8 years of age receiving Singulair (Montelukast sodium) , the following events not previously observed with the use of Singulair (Montelukast sodium) in this age group occurred with a frequency ≥2% and more frequently than in pediatric patients who received placebo, regardless of causality assessment: headache, rhinitis (infective), varicella, gastroenteritis, atopic dermatitis, acute bronchitis, tooth infection, skin infection, and myopia.
Safety and effectiveness in pediatric patients younger than 12 months of age with asthma have not been established.
Singulair (Montelukast sodium) has been evaluated for safety in 175 pediatric patients 6 to 23 months of age. The safety profile of Singulair (Montelukast sodium) in a 6-week, double-blind, placebo-controlled clinical study was generally similar to the safety profile in adults and pediatric patients 2 to 14 years of age. Singulair (Montelukast sodium) administered once daily at bedtime was generally well tolerated. In pediatric patients 6 to 23 months of age receiving Singulair (Montelukast sodium) , the following events occurred with a frequency ≥2% and more frequently than in pediatric patients who received placebo, regardless of causality assessment: upper respiratory infection, wheezing; otitis media; pharyngitis, tonsillitis, cough; and rhinitis. The frequency of less common adverse events was comparable between Singulair (Montelukast sodium) and placebo.
The following additional adverse reactions have been reported in post-marketing use:
Blood and lymphatic system disorders: increased bleeding tendency
Immune system disorders: hypersensitivity reactions including anaphylaxis, very rarely hepatic eosinophilic infiltration
Psychiatric disorders: agitation including aggressive behavior, anxiousness, dream abnormalities and hallucinations, depression, insomnia, irritability, restlessness, suicidal thinking and behavior (including suicide), tremor
Nervous system disorders: drowsiness, paraesthesia/hypoesthesia, very rarely seizures
Cardiac disorders: palpitations
Respiratory, thoracic and mediastinal disorders: epistaxis
Gastrointestinal disorders: diarrhea, dyspepsia, nausea, very rarely pancreatitis, vomiting
Hepatobiliary disorders: Rare cases of cholestatic hepatitis, hepatocellular liver-injury, and mixed-pattern liver injury have been reported in patients treated with Singulair (Montelukast sodium) . Most of these occurred in combination with other confounding factors, such as use of other medications, or when Singulair (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 nodosum, pruritus, urticaria
Musculoskeletal and connective tissue disorders: arthralgia, myalgia including muscle cramps
General disorders and administration site conditions: edema
In rare cases, patients with asthma on therapy with Singulair (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 usually, but not always, have been 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 Singulair (Montelukast sodium) and these underlying conditions has not been established (see ).
Singulair (Montelukast sodium) Overdosage
No mortality occurred following single oral doses of montelukast up to 5000 mg/kg in mice (estimated exposure was approximately 335 and 210 times the AUC for adults and children, respectively, at the maximum recommended daily oral dose) and rats (estimated exposure was approximately 230 and 145 times the AUC for adults and children, respectively, at the maximum recommended daily oral dose).
No specific information is available on the treatment of overdosage with Singulair (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 Singulair (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 Singulair (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.
Singulair (Montelukast sodium) Dosage And Administration
The dosage for adults and adolescents 15 years of age and older is one 10-mg tablet.
The dosage for pediatric patients 6 to 14 years of age is one 5-mg chewable tablet.
The dosage for pediatric patients 2 to 5 years of age is one 4-mg chewable tablet or one packet of 4-mg oral granules.
The dosage for pediatric patients 6 to 23 months of age is one packet of 4-mg oral granules.
Singulair (Montelukast sodium) How Supplied
No. 3841 — Singulair (Montelukast sodium) Oral Granules, 4 mg, are white granules with 500 mg net weight, packed in a child-resistant foil packet. They are supplied as follows:
No. 3796 — Singulair (Montelukast sodium) Tablets, 4 mg, are pink, oval, bi-convex-shaped chewable tablets, with code MRK 711 on one side and Singulair (Montelukast sodium) on the other. They are supplied as follows:
No. 3760 — Singulair (Montelukast sodium) Tablets, 5 mg, are pink, round, bi-convex-shaped chewable tablets, with code MRK 275 on one side and Singulair (Montelukast sodium) on the other. They are supplied as follows:
No. 3761 — Singulair (Montelukast sodium) Tablets, 10 mg, are beige, rounded square-shaped, film-coated tablets, with code MRK 117 on one side and Singulair (Montelukast sodium) on the other. They are supplied as follows:
Singulair (Montelukast sodium) Patient Information
Read this information before you start taking Singulair (Montelukast sodium) . Also, read the leaflet you get each time you refill Singulair (Montelukast sodium) , since there may be new information in the leaflet since the last time you saw it. This leaflet does not take the place of talking with your doctor about your medical condition and/or your treatment.
