4.1. Therapeutic indications

Montelukast 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 β-agonists provide inadequate clinical control of asthma.

Montelukast 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).

Montelukast 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 Montelukast 4 mg granules formulation is not recommended below 6 months of age.

Administration of Montelukast granules:

Montelukast 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 Montelukast granules must be administered immediately (within 15 minutes). If mixed with food, Montelukast granules must not be stored for future use. Montelukast granules are not intended to be dissolved in liquid for administration. However, liquids may be taken subsequent to administration. Montelukast granules can be administered without regard to the timing of food ingestion.

General recommendations

The therapeutic effect of Montelukast on parameters of asthma control occurs within one day. Patients should be advised to continue taking Montelukast 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.

Montelukast 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 than 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 follow-up (usually within one month), the need for an additional or different anti-inflammatory therapy based on the step system for asthma therapy should be evaluated. Patients should be periodically evaluated for their asthma control.

Montelukast 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 Montelukast in relation to other treatments for asthma

When treatment with Montelukast is used as add-on therapy to inhaled corticosteroids, Montelukast 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 Montelukast 4 mg granules to children less than 6 months of age. The safety and efficacy of Montelukast 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

The diagnosis of persistent asthma in very young children (6 months – 2 years) should be established by a paediatrician or pulmonologist.

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 β-agonist should be used. Patients should seek their doctors' advice as soon as possible if they need more inhalations of short-acting β-agonists than usual.

Montelukast should not be abruptly substituted 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 aspirin-sensitive asthma to avoid taking aspirin and other non-steroidal anti-inflammatory drugs.

Neuropsychiatric events such as behavioural changes, depression and suicidality have been reported in all age groups taking montelukast (see section 4.8). The symptoms may be serious and continue if the treatment is not withdrawn. Therefore the treatment with montelukast should be discontinued if neuropsychiatric symptoms occur during treatment.

Advise patients and/or caregivers to be alert for neuropsychiatric events and instruct them to notify their physician if these changes in behaviour occur.

This medicine contains less than 1 mmol sodium (23 mg) per sachet, that is to say essentially 'sodium-free'.

4.5. Interaction 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 metabolised 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 metabolised 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 co-administration 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. Co-administration 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.

Montelukast 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.

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

Fertility

There are no data on fertility in humans available.

4.7. Effects on ability to drive and use machines

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

4.8. Undesirable effects

Montelukast has been evaluated in clinical studies in patients with persistent asthma as follows:

▪ 10 mg film-coated tablets in approximately 4,000 adult and adolescent patients 15 years of age and older

▪ 5 mg chewable tablets in approximately 1,750 paediatric patients 6 to 14 years of age

▪ 4 mg chewable tablets in 851 paediatric patients 2 to 5 years of age, and

▪ 4 mg granules in 175 paediatric patients 6 months to 2 years of age.

Montelukast has been evaluated in a clinical study in patients with intermittent asthma as follows:

▪ 4 mg granules and chewable tablets in 1,038 paediatric patients 6 months to 5 years of age

The following drug-related adverse reactions in clinical studies were reported commonly (≥1/100 to <1/10) in patients treated with Montelukast and at a greater incidence than in patients treated with placebo:

Body System Class

Adult and Adolescent Patients

15 years and older

(two 12-week studies; n=795)

Paediatric Patients

6 to 14 years old

(one 8-week study; n=201)

(two 56-week studies; n=615)

Paediatric Patients

2 to 5 years old

(one 12-week study; n=461)

(one 48-week study; n=278)

Paediatric Patients

6 months up to 2 years old

(one 6-week study; n=175)

Nervous system disorders

headache

headache

hyperkinesia

Respiratory, thoracic, and mediastinal disorders

asthma

Gastro-intestinal disorders

abdominal pain

abdominal pain

diarrhoea

Skin and subcutaneous tissue disorders

eczematous dermatitis, rash

General disorders and administration site conditions

thirst

With prolonged treatment in clinical trials with a limited number of patients for up to 2 years for adults, and up to 12 months for paediatric patients 6 to 14 years of age, the safety profile did not change.

Cumulatively, 502 paediatric patients 2 to 5 years of age were treated with Montelukast for at least 3 months, 338 for 6 months or longer, and 534 patients for 12 months or longer. With prolonged treatment, the safety profile did not change in these patients either.

The safety profile in paediatric patients 6 months to 2 years of age did not change with treatment up to 3 months.

Tabulated list of Adverse Reactions

Adverse reactions reported in post-marketing use are listed, by System Organ Class and specific Adverse Reactions, in the table below. Frequency Categories were estimated based on relevant clinical trials.

System Organ Class

Adverse Reactions

Frequency Category*

Infections and infestations

upper respiratory infection†

Very Common

Blood and lymphatic system disorders

increased bleeding tendency

Rare

thrombocytopenia

Very Rare

Immune system disorders

hypersensitivity reactions including anaphylaxis

Uncommon

hepatic eosinophilic infiltration

Very Rare

Psychiatric disorders

dream abnormalities including nightmares, insomnia, somnambulism, anxiety, agitation including aggressive behaviour or hostility, depression, psychomotor hyperactivity (including irritability, restlessness, tremor§)

Uncommon

disturbance in attention, memory impairment, tic

Rare

hallucinations, disorientation, suicidal thinking and behaviour (suicidality), obsessive-compulsive symptoms, dysphemia

Very Rare

Nervous system disorders

dizziness, drowsiness, paraesthesia/hypoesthesia, seizure

Uncommon

Cardiac disorders

palpitations

Rare

Respiratory, thoracic and mediastinal disorders

epistaxis

Uncommon

Churg-Strauss Syndrome (CSS) (see section 4.4)

Very Rare

pulmonary eosinophilia

Very Rare

Gastro-intestinal disorders

diarrhoea‡, nausea‡, vomiting‡

Common

dry mouth, dyspepsia

Uncommon

Hepatobiliary disorders

elevated levels of serum transaminases (ALT, AST)

Common

hepatitis (including cholestatic, hepatocellular, and mixed-pattern liver injury).

Very Rare

Skin and subcutaneous tissue disorders

rash‡

Common

bruising, urticaria, pruritus

Uncommon

angiooedema

Rare

erythema nodosum, erythema multiforme

Very Rare

Musculoskeletal and connective tissue disorders

arthralgia, myalgia including muscle cramps

Uncommon

Renal and urinary disorders

enuresis in children

Uncommon

General disorders and administration site conditions

pyrexia‡

Common

asthenia/fatigue, malaise, oedema

Uncommon

*Frequency Category: Defined for each Adverse Reaction by the incidence reported in the clinical trials data base: Very Common (≥1/10), Common (≥1/100 to <1/10), Uncommon (≥1/1,000 to <1/100), Rare (≥1/10,000 to <1/1,000), Very Rare (<1/10,000).

† This adverse experience, reported as Very Common in the patients who received Montelukast, was also reported as Very Common in the patients who received placebo in clinical trials.

‡ This adverse experience, reported as Common in the patients who received Montelukast, was also reported as Common in the patients who received placebo in clinical trials.

§ Frequency Category: Rare

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

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 one week without clinically important adverse experiences.

There have been reports of acute overdose in post-marketing experience and clinical studies with Montelukast. These include reports in adults and children with a dose as high as 1,000 mg (approximately 61 mg/kg in a 42 month old child). The clinical and laboratory findings observed were consistent with the safety profile in adults and paediatric patients. There were no adverse experiences in the majority of overdose reports.

Symptoms of overdose

The most frequently occurring adverse experiences were consistent with the safety profile of Montelukast and included abdominal pain, somnolence, thirst, headache, vomiting, and psychomotor hyperactivity.

Management of overdose

No specific information is available on the treatment of overdose with montelukast. It is not known whether montelukast is dialysable by peritoneal- or haemo-dialysis.