SINGULAIR PAEDIATRIC 4 MG GRANULES - summary of medicine characteristics

Singulair Paediatric 4mg Granules

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

One sachet of granules contains montelukast sodium, which is equivalent to 4 mg montelukast.

Excipient with known effect: This medicine contains less than 1 mmol sodium (23 mg) per sachet, that is to say essentially ‘sodium-free’.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

GRANULES.

White granular, coarse, free-flowing homogenous solid with no extraneous particles present.

4.1 Therapeutic indications

Singulair is indicated in the treatment of asthma as add-on therapy in those 6 months to 5 year old patients with mild to moderate persistent asthma who are inadequately controlled on inhaled corticosteroids and in whom “as-needed” short acting P-agonists provide inadequate clinical control of asthma.

Singulair may also be an alternative treatment option to low-dose inhaled corticosteroids for 2 to 5 year old patients with mild persistent asthma who do not have a recent history of serious asthma attacks that required oral corticosteroid use, and who have demonstrated that they are not capable of using inhaled corticosteroids (see section 4.2).

Singulair is also indicated in the prophylaxis of asthma from 2 years of age and older in which the predominant component is exercise-induced bronchoconstric­tion.

4.2 Posology and method of administration

Posology

This medicinal product is to be given to a child under adult supervision. The recommended dose for paediatric patients 6 months to 5 years of age is one sachet of 4 mg granules daily to be taken in the evening. No dosage adjustment within this age group is necessary. Efficacy data from clinical trials in paediatric patients 6 months to 2 years of age with persistent asthma are limited. Patients should be evaluated after 2 to 4 weeks for response to montelukast treatment. Treatment should be discontinued if a lack of response is observed. The Singulair 4 mg granules formulation is not recommended below 6 months of age.

Administration of Singulair granules:

Singulair granules can be administered either directly in the mouth or mixed with a spoonful of cold or room temperature soft food (e.g., applesauce, ice cream, carrots and rice). The sachet should not be opened until ready to use. After opening the sachet, the full dose of Singulair granules must be administered immediately (within 15 minutes). If mixed with food, Singulair granules must not be stored for future use. Singulair granules are not intended to be dissolved in liquid for administration. However, liquids may be taken subsequent to administration. Singulair granules can be administered without regard to the timing of food ingestion.

General recommendations

The therapeutic effect of Singulair on parameters of asthma control occurs within one day. Patients should be advised to continue taking Singulair even if their asthma is under control, as well as during periods of worsening asthma.

No dosage adjustment is necessary for patients with renal insufficiency, or mild to moderate hepatic impairment. There are no data on patients with severe hepatic impairment. The dosage is the same for both male and female patients.

Singulair as an alternative treatment option to low-dose inhaled corticosteroids for mild, persistent asthma

Montelukast is not recommended as monotherapy in patients with moderate persistent asthma. The use of montelukast as an alternative treatment option to low-dose inhaled corticosteroids for children 2 to 5 years old with mild persistent asthma should only be considered for patients who do not have a recent history of serious asthma attacks that required oral corticosteroid use and who have demonstrated that they are not capable of using inhaled corticosteroids (see section 4.1). Mild persistent asthma is defined as asthma symptoms more than once a week but less that once a day, nocturnal symptoms more than twice a month but less than once a week, normal lung function between episodes. If satisfactory control of asthma is not achieved at followup (usually within one month), the need for an additional or different antiinflammatory therapy based on the step system for asthma therapy should be evaluated. Patients should be periodically evaluated for their asthma control.

Singulair as prophylaxis of asthma for 2 to 5 year old patients in whom the predominant component is exercise-induced bronchoconstriction

In 2 to 5 year old patients, exercise-induced bronchoconstriction may be the predominant manifestation of persistent asthma that requires treatment with inhaled corticosteroids. Patients should be evaluated after 2 to 4 weeks of treatment with montelukast. If satisfactory response is not achieved, an additional or different therapy should be considered.

Therapy with Singulair in relation to other treatments for asthma

When treatment with Singulair is used as add-on therapy to inhaled corticosteroids, Singulair should not be abruptly substituted for inhaled corticosteroids (see section 4.4).

10 mg film-coated tablets are available for adults and adolescents 15 years of age and older.

Paediatric population

Do not give Singulair 4 mg granules to children less than 6 months of age. The safety and efficacy of Singulair 4 mg granules in children less than 6 months of age has not been established.

5 mg chewable tablets are available for paediatric patients 6 to 14 years of age. 4 mg chewable tablets are available as an alternative formulation for paediatric patients 2 to 5 years of age.

Method of administration Oral use.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

4.4 Special warnings and precautions for use

Patients should be advised never to use oral montelukast to treat acute asthma attacks and to keep their usual appropriate rescue medication for this purpose readily available. If an acute attack occurs, a short-acting inhaled P—agonist should be used. Patients should seek their doctors’ advice as soon as possible if they need more inhalations of short-acting P-agonists than usual.

Montelukast should not be substituted abruptly for inhaled or oral corticosteroids.

There are no data demonstrating that oral corticosteroids can be reduced when montelukast is given concomitantly.

In rare cases, patients on therapy with anti-asthma agents including montelukast 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 cases have been sometimes associated with the reduction or withdrawal of oral corticosteroid therapy. Although a causal relationship with leukotriene receptor antagonism has not been established, physicians should be alert to eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy presenting in their patients. Patients who develop these symptoms should be reassessed and their treatment regimens evaluated.

Treatment with montelukast does not alter the need for patients with aspirinsensitive asthma to avoid taking aspirin and other non-steroidal anti-inflammatory drugs.

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Neuropsychiatric events have been reported in adults, adolescents, and children taking Singulair (see section 4.8). Patients and physicians should be alert for neuropsychiatric events. Patients and/or caregivers should be instructed to notify their physician if these changes occur. Prescribers should carefully evaluate the risks and benefits of continuing treatment with Singulair if such events occur.

4.5 Interactions with other medicinal products and other forms of interaction

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

The area under the plasma concentration curve (AUC) for montelukast was decreased approximately 40% in subjects with co-administration of phenobarbital. Since montelukast is metabolised by CYP 3A4, 2C8, and 2C9, caution should be exercised, particularly in children, when montelukast is coadministered with inducers of CYP 3A4, 2C8, and 2C9, such as phenytoin, phenobarbital and rifampicin.

In vitro studies have shown that montelukast is a potent inhibitor of CYP 2C8. However, data from a clinical drug-drug interaction study involving montelukast and rosiglitazone (a probe substrate representative of medicinal products primarily metabolized by CYP 2C8) demonstrated that montelukast does not inhibit CYP 2C8 in vivo. Therefore, montelukast is not anticipated to markedly alter the metabolism of medicinal products metabolized by this enzyme (e.g., paclitaxel, rosiglitazone, and repaglinide).

In vitro studies have shown that montelukast is a substrate of CYP 2C8, and to a less significant extent, of 2C9, and 3A4. In a clinical drug-drug interaction study involving montelukast and gemfibrozil (an inhibitor of both CYP 2C8 and 2C9) gemfibrozil increased the systemic exposure of montelukast by 4.4-fold. No routine dosage adjustment of montelukast is required upon coadministration with gemfibrozil or other potent inhibitors of CYP 2C8, but the physician should be aware of the potential for an increase in adverse reactions.

Based on in vitro data, clinically important drug interactions with less potent inhibitors of CYP 2C8 (e.g., trimethoprim) are not anticipated. Coadministration of montelukast with itraconazole, a strong inhibitor of CYP 3A4, resulted in no significant increase in the systemic exposure of montelukast.

4.6 Fertility, pregnancy and lactation

Pregnancy

Animal studies do not indicate harmful effects with respect to effects on pregnancy or embryonal/foetal development.

Available data from published prospective and retrospective cohort studies with montelukast use in pregnant women evaluating major birth defects have not established a drug-associated risk. Available studies have methodologic limitations, including small sample size, in some cases retrospective data collection, and inconsistent comparator groups.

Singulair may be used during pregnancy only if it is considered to be clearly essential.

Breast-feeding

Studies in rats have shown that montelukast is excreted in milk (see section 5.3). It is unknown whether montelukast/me­tabolites are excreted in human milk.

Singulair may be used in breast-feeding mothers only if it is considered to be clearly essential.

4.7 Effects on ability to drive and use machines

Singulair has no or negligible influence on the ability to drive and use machines. However, individuals have reported drowsiness or dizziness.

4.8 Undesirable effects

5.  PHARMACOLOGICAL PROPERTIES

5.2 Pharmacokinetic properties

Absorption

Montelukast is rapidly absorbed following oral administration. For the 10 mg film-coated tablet, the mean peak plasma concentration (Cmax) is achieved 3 hours (Tmax) after administration in adults in the fasted state. The mean oral bioavailability is 64%. The oral bioavailability and Cmax are not influenced by a standard meal. 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 Cmax is achieved in 2 hours after administration in adults in the fasted state. The mean oral bioavailability is 73% and is decreased to 63% by a standard meal.

After administration of the 4 mg chewable tablet to paediatric patients 2 to 5 years of age in the fasted state, Cmax is achieved 2 hours after administration. The mean Cmax is 66% higher while mean Cmin is lower than in adults receiving a 10 mg tablet.

The 4 mg granule formulation is bioequivalent to the 4 mg chewable tablet when administered to adults in the fasted state. In paediatric patients 6 months to 2 years of age, Cmax is achieved 2 hours after administration of the 4 mg granules formulation. Cmax is nearly 2-fold greater than in adults receiving a 10 mg tablet. The co-administration of applesauce or a high-fat standard meal with the granule formulation did not have a clinically meaningful effect on the pharmacokinetics of montelukast as determined by AUC(1225.7 vs 1223.1 ng.hr/mL with and without applesauce, respectively, and 1191.8 vs 1148.5 ng.hr/mL with and without a high-fat standard meal, respectively).

Distribution

Montelukast is more than 99% bound to plasma proteins. The steady-state volume of distribution of montelukast averages 8–11 litres. Studies in rats with radiolabelled montelukast indicate minimal distribution across the blood-brain barrier. In addition, concentrations of radiolabelled material at 24 hours post-dose were minimal in all other tissues.

Biotransformation

Montelukast is extensively metabolized. In studies with therapeutic doses, plasma concentrations of metabolites of montelukast are undetectable at steady state in adults and children.

Cytochrome P450 2C8 is the major enzyme in the metabolism of montelukast. Additionally, CYP 3A4 and 2C9 may have a minor contribution, although itraconazole, an inhibitor of CYP 3A4, was shown not to change pharmacokinetic variables of montelukast in healthy subjects that received 10 mg montelukast daily. Based on in vitro results in human liver microsomes, therapeutic plasma concentrations of montelukast do not inhibit cytochromes P450 3A4, 2C9, 1A2, 2A6, 2C19, or 2D6. The contribution of metabolites to the therapeutic effect of montelukast is minimal.

Elimination

The plasma clearance of montelukast averages 45 ml/min in healthy adults. Following an oral dose of radiolabelled 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 that montelukast and its metabolites are excreted almost exclusively via the bile.

Characteristics in Patients

No dosage adjustment is necessary for the elderly or mild to moderate hepatic insufficiency. Studies in patients with renal impairment have not been undertaken. Because montelukast and its metabolites are eliminated by the biliary route, no dose adjustment is anticipated to be necessary in patients with renal impairment. There are no data on the pharmacokinetics of montelukast in patients with severe hepatic insufficiency (Child-Pugh score >9).

With high doses of montelukast (20– and 60-fold the recommended adult dose), a decrease in plasma theophylline concentration was observed. This effect was not seen at the recommended dose of 10 mg once daily.

5.3 Preclinical safety data

In animal toxicity studies, minor serum biochemical alterations in ALT, glucose, phosphorus and triglycerides were observed which were transient in nature. The signs of toxicity in animals were increased excretion of saliva, gastrointestinal symptoms, loose stools and ion imbalance. These occurred at dosages which provided >17-fold the systemic exposure seen at the clinical dosage. In monkeys, the adverse effects appeared at doses from 150 mg/kg/day (>232-fold the systemic exposure seen at the clinical dose). In animal studies, montelukast did not affect fertility or reproductive performance at systemic exposure exceeding the clinical systemic exposure by greater than 24-fold. A slight decrease in pup body weight was noted in the female fertility study in rats at 200 mg/kg/day (>69-fold the clinical systemic exposure). In studies in rabbits, a higher incidence of incomplete ossification, compared with concurrent control animals, was seen at systemic exposure >24-fold the clinical systemic exposure seen at the clinical dose. No abnormalities were seen in rats. Montelukast has been shown to cross the placental barrier and is excreted in breast milk of animals.

No deaths occurred following a single oral administration of montelukast sodium at doses up to 5,000 mg/kg in mice and rats (15,000 mg/m2 and 30,000 mg/m2 in mice and rats, respectively), the maximum dose tested. This dose is equivalent to 25,000 times the recommended daily adult human dose (based on an adult patient weight of 50 kg).

Montelukast was determined not to be phototoxic in mice for UVA, UVB or visible light spectra at doses up to 500 mg/kg/day (approximately >200-fold based on systemic exposure).

Montelukast was neither mutagenic in in vitro and in vivo tests nor tumorigenic in rodent species.

6.1 List of excipients

Mannitol (E 421)

Hyprolose (E 463)

Magnesium stearate

6.2 Incompatibilities

Not applicable

6.3 Shelf-life

2 years.

6.4 Special precautions for storage

Do not store above 25°C. Store in the original package in order to protect from light and moisture.

6.5 Nature and contents of container

Packaged in polyethylene/a­luminium/poly­ester sachet in:

Cartons of 7, 20, 28 and 30 sachets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7. MARKETING AUTHORISATION HOLDER

Merck Sharp & Dohme Ltd

Hertford Road

Hoddesdon

Hertfordshire

EN11 9BU

United Kingdom

8. MARKETING AUTHORISATION NUMBER

PL 00025/0440

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 14 February 2003

Date of latest renewal: 25 August 2012

10