Manufacturers Information Sheet SINGULAIR

montelukast sodium

10mg tablet
5mg chewable tablet

Presentation

10mg tablet: A beige rounded square film-coated tablet engraved with SINGULAIR on one side and MSD117 on the other, containing 10mg of montelukast sodium. Dimensions: 7.87 x 7.87mm.

5mg chewable tablet: A pink round biconvex chewable tablet with a cherry flavour engraved SINGULAIR on one side and MSD275 on the other, containing 5mg of montelukast sodium. Dimensions: 9.525mm diameter.

Therapeutic Class

SINGULAIR (montelukast sodium) is a selective and orally active leukotriene receptor antagonist that specifically inhibits cysteinyl leukotriene CysLT₁ receptor

Indications

SINGULAIR is indicated in adult and paediatric patients for the prophylaxis and chronic treatment of asthma, including the prevention of day- and night-time symptoms.

Dosage and Administration

Adults 15 Years of Age and Older
The dosage for adults 15 years of age and older is one 10-mg tablet daily to be taken at bedtime.

Paediatric Patients 6 to 14 Years of Age
The dosage for paediatric patients 6 to 14 years of age is one 5-mg chewable tablet daily to be taken at bedtime. No dosage adjustment within this age group is necessary. Safety and effectiveness in paediatric patients younger than 6 years of age have not been established.

General Recommendations
The therapeutic effect of SINGULAIR on parameters of asthma control occurs within one day. SINGULAIR may be taken with or without food. Patients should be advised to continue taking SINGULAIR while their asthma is controlled, as well as during periods of worsening asthma.

No dosage adjustment is necessary for the elderly, for patients with renal insufficiency, or mild-to-moderate hepatic impairment, or for patients of either gender.

Therapy with SINGULAIR in Relation to Other Treatments for Asthma
SINGULAIR can be added to a patient's existing treatment regimen.

Reduction in Concomitant Therapy:

Bronchodilator Treatments: SINGULAIR can be added to the treatment regimen of patients who are not adequately controlled on bronchodilator alone. When a clinical response is evident (usually after the first dose), the patient's bronchodilator therapy can be reduced as tolerated.

Inhaled Corticosteroids: Treatment with SINGULAIR provides additional clinical benefit to patients treated with inhaled corticosteroids. A reduction in the corticosteroid dose can be made as tolerated. The dose should be reduced gradually with medical supervision. In some patients, the dose of inhaled corticosteroids can be tapered off completely. SINGULAIR should not be abruptly substituted for inhaled corticosteroids.

Limited data suggest that SINGULAIR may provide additional clinical benefit in patients with oral corticosteroids.

Contraindications

Hypersensitivity to any component of this product

Warnings and Precautions

The efficacy of oral SINGULAIR for the treatment of acute asthma attacks has not been established. Therefore, oral tablets of SINGULAIR should not be used to treat acute asthma attacks. Patients should be advised to have appropriate rescue medication available.

While the dose of concomitant inhaled corticosteroid may be reduced gradually under medical supervision, SINGULAIR should not be abruptly substituted for inhaled or oral corticosteroids.

The reduction in systemic corticosteroid dose in patients receiving anti-asthma agents including leukotriene receptor antagonists has been followed in rare cases by the occurrence of one or more of the following: eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy sometimes diagnosed as Churg-Strauss syndrome, a systemic eosinophilic vasculitis. Although a causal relationship with leukotriene receptor antagonism has not been established, caution and appropriate clinical monitoring are recommended when systemic corticosteroid reduction is considered in patients receiving SINGULAIR.

Pregnancy

SINGULAIR has not been studied in pregnant women. SINGULAIR should be used during pregnancy only if clearly needed.

Nursing Mothers

It is not known if SINGULAIR is excreted in human milk. Because many medicines are excreted in human milk, caution should be exercised when SINGULAIR is given to a nursing mother.

Paediatric Use

SINGULAIR has been studied in paediatric patients 6 to 14 years of age (see Dosage and Administration). Safety and effectiveness in paediatric patients younger than 6 years of age have not been studied.

Use in the Elderly

In clinical studies, there were no age-related differences in the efficacy or safety profiles of SINGULAIR.

Renal/Hepatic Impairment

No dosage adjustment is required for patients with renal insufficiency or mild to moderate hepatic impairment. (See Uses, Pharmacokinetics, Characteristics in Patients).

Carcinogenicity and Mutagenicity

There were no significant results seen with montelukast sodium in carcinogenicity or mutagenicity studies

Reproduction

There were no significant results in reproduction studies conducted with montelukast sodium

Development

In developmental toxicity studies, there were no treatment related adverse effects at doses up to 400 mg/kg/day in rats and up to 100 mg/kg/day in rabbits. Foetal exposure of montelukast sodium in rats and rabbits does occur and significant concentrations of medicine were observed in milk of lactating rats.

Effect on Ability to Drive and Use Machines

There is no evidence that SINGULAIR affects the ability to drive and use machines.

Adverse Effects

SINGULAIR has been generally well tolerated. Side effects, which usually were mild, generally did not require discontinuation of therapy. The overall incidence of adverse effects (including laboratory adverse effects) reported with SINGULAIR was comparable to placebo.

Adults 15 Years of Age and Older
SINGULAIR has been evaluated in approximately 2600 adult patients 15 years of age and older in clinical studies. In two similarly designed, 12-week placebo-controlled clinical trials, only abdominal pain and headache were reported as medicine-related in ( 1% of patients treated with SINGULAIR and at a greater incidence than in patients treated with placebo. The incidences of these events were not significantly different in the two treatment groups.

Cumulatively, 544 patients were treated with SINGULAIR for at least 6 months, 253 for one year and 21 for 2 years in clinical trials. With prolonged treatment, the adverse experience profile did not change.

Paediatric Patients 6 to 14 Years of Age
SINGULAIR has also been evaluated in approximately 320 paediatric patients 6 to 14 years of age. In an 8-week, placebo-controlled clinical trial, only headache was reported as medicine-related in > 1% of patients treated with SINGULAIR and at a greater incidence than in patients treated with placebo. The incidence was not significantly different in the two treatment groups.

Cumulatively, 143 paediatric patients were treated with SINGULAIR for at least 3 months and 44 for 6 months or longer. With prolonged treatment, the adverse experience profile did not change.

Post-Marketing Experience

The following adverse reactions have been reported in post-marketing use: hypersensitivity reactions, including anaphylaxis, angioedema, pruritus, and urticaria and very rarely hepatic eosinophilic infiltration), dream abnormalities, drowsiness, irritability, and restlessness.

Interactions

SINGULAIR may be administered with other therapies routinely used in the prophylaxis and chronic treatment of asthma. In medicine-interactions studies, the recommended clinical dose of montelukast did not have clinically important effects on the pharmacokinetics of the following medicines: theophylline, prednisone, prednisolone, oral contraceptives (ethinyl estradiol/norethindrone 35/1), terfenadine, digoxin and warfarin.

Although additional specific interaction studies were not performed, SINGULAIR was used concomitantly with a wide range of commonly prescribed medicines in clinical studies without evidence of clinical adverse interactions. These medications included thyroid hormones, sedative hypnotics, nonsteroidal anti-inflammatory agents, benzodiazepines and decongestants.

The area under the plasma concentration curve (AUC) for montelukast was decreased approximately 40% in subjects with co-administration of phenobarbital. No dosage adjustment for SINGULAIR is recommended.

SINGULAIR may be taken with or without food. There are no data available on the use of SINGULAIR and alcohol.

Overdosage

No specific information is available on the treatment of overdosage with SINGULAIR. In chronic asthma studies, SINGULAIR has been administered at doses up to 200 mg/day to patients for 22 weeks and in short-term studies, up to 900 mg/day to patients for approximately one week without clinically important adverse experiences.

It is not known whether montelukast is dialysable by peritoneal- or haemodialysis.

Actions

Mechanism of Action

The cysteinyl leukotrienes (LTC₄, LTD₄, LTE₄), are potent inflammatory eicosanoids released from various cells including mast cells and eosinophils. These important pro-asthmatic mediators bind to cysteinyl leukotriene receptors (CysLT) found in the human airway and cause a number of airway actions, including bronchoconstriction, mucous secretion, vascular permeability, and eosinophil recruitment.

Montelukast is a potent, orally active compound that significantly improves parameters of asthmatic inflammation. Based on biochemical and pharmacological bioassays, it binds with high affinity and selectivity to the CysLT₁ receptor (in preference to other pharmacologically important airway receptors such as the prostanoid, cholinergic, or b-adrenergic receptor). Montelukast potently inhibits physiologic actions of LTC₄, LTD₄, and LTE₄ at the CysLT₁ receptor without any agonist activity.

A second cysteinyl leukotriene receptor (CysLT₂) is present in the lung but appears to be confined to blood vessels. To date, neither receptor has been cloned, so the presence of CysLT receptors has been delineated principally through receptor binding and pharmacological assays. Montelukast is not believed to antagonise the CysLT₂ receptor.

Pharmacokinetics

Absorption

Montelukast is rapidly and nearly completely absorbed following oral administration. For the 10-mg film-coated tablet, the mean peak plasma concentration (C_max) is achieved 3 hours (T_max) after administration in adults in the fasted state. The mean oral bioavailability is 64%. The oral bioavailability and C_max are not influenced by a standard meal. Safety and efficacy were demonstrated in clinical trials where the 10-mg film-coated tablet was administered without regard to the timing of food ingestion.

For the 5-mg chewable tablet, the C_max is achieved 2 hours after administration in adults in the fasted state. The mean oral bioavailability is 73%. Food does not have a clinically important influence with chronic administration.

Distribution

Montelukast is more than 99% bound to plasma proteins. The steady-state volume of distribution of montelukast averages 8 to 11 litres. 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 metabolised. In studies with therapeutic doses, plasma concentrations of metabolites of montelukast are undetectable at steady state in adults and paediatric patients.

In vitro studies using human liver microsomes indicate that cytochrome P450 3A4 and 2C9 are involved in the metabolism of montelukast. Based on further in vitro results in human liver microsomes, therapeutic plasma concentrations of montelukast do not inhibit cytochromes P450 3A4, 2C9, 1A2, 2A6, 2C19, or 2D6.

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 faecal collections and <0.2% was recovered in urine. Coupled with estimates of montelukast oral bioavailability, this indicates montelukast and its metabolites are excreted almost exclusively via the bile.

In several studies, the mean plasma half-life of montelukast ranged from 2.7 to 5.5 hours in healthy young adults. The pharmacokinetics of montelukast are nearly linear for oral doses up to 50 mg. No difference in pharmacokinetics was noted between dosing in the morning or in the evening. During once-daily dosing with 10-mg montelukast, there is little accumulation of the parent medicine in plasma (~14%).

Characteristics in Patients

Gender

The pharmacokinetics of montelukast are similar in males and females.

Elderly

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.

Race

Pharmacokinetic differences due to race have not been studied. In clinical studies, there do not appear to be any differences in clinically important effects.

Hepatic Insufficiency

Patients with mild-to-moderate hepatic insufficiency and clinical evidence of cirrhosis had evidence of decreased metabolism of montelukast resulting in approximately 41% higher mean montelukast area under the plasma concentration curve (AUC) following a single 10-mg dose. The elimination of montelukast is 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. There are no clinical data in patients with severe hepatic insufficiency (Child-Pugh score > 9).

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.

Adolescents and Paediatric Patients

The plasma concentration profile of montelukast following the 10-mg film-coated tablet is similar in adolescents ³15 years old and young adults. The 10-mg film coated tablet is recommended for use in patients ³15 years old.

Pharmacokinetic studies using either the chewable tablet or film-coated tablet show that the plasma profile of the 5-mg chewable tablet in paediatric patients 6 to 14 years of age is similar to that of the 10-mg film-coated tablet in adults. The 5-mg chewable tablet should be used in paediatric patients 6 to 14 years of age.

Pharmaceutical Precautions

Store the 10-mg film-coated tablets and the 5-mg chewable tablets at room temperature 15-30°C (59-86°F), protected from moisture and light.

Medicine Classification

Prescription Medicine.

Package Quantities

SINGULAIR Tablets/Chewable Tablets are available in blister packs of 28 tablets.

Further Information

Chemistry

SINGULAIR, (montelukast sodium) is described chemically as [R-(E)]-1-[[[1-[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl) phenyl]propyl]thio]methyl]cyclopropane acetic acid, monosodium salt.

The empirical formula is C₃₅H₃₅ClNNaO₃S, and its molecular weight is 608.18.

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.

Composition

Each 10-mg film-coated tablet contains 10.4 mg montelukast sodium, which is the molar equivalent to 10.0 mg of free acid. Each 5-mg chewable tablet contains 5.2 mg montelukast sodium, which is the molar equivalent to 5.0 mg of free acid.

Each 10-mg film-coated tablet contains 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 iron oxide, yellow iron oxide, and carnauba wax.

Each 5-mg chewable tablet contains the following inactive ingredients: mannitol, microcrystalline cellulose, hydroxypropyl cellulose, red ferric oxide, croscarmellose sodium, cherry flavour, aspartame, and magnesium stearate.