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SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Montelukast 10 mg film-coated tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains montelukast sodium, which is equivalent to 10 mg montelukast.

Excipient: Lactose monohydrate 88.62 mg per tablet For the full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Film-coated tablet.

Beige coloured, rounded square shaped, film-coated tablets debossed with ‘X’ on one side and ‘54’ on other side. The tablets are 8.1 mm in diameter.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Montelukast is indicated in the treatment of asthma as add-on therapy in adolescents and adults from 15 years of age with mild to moderate persistent asthma who are inadequately controlled on inhaled corticosteroids and in whom “as-needed” short acting beta-agonists provide inadequate clinical control of asthma. In those asthmatic patients in whom Montelukast is indicated in asthma, Montelukast can also provide symptomatic relief of seasonal allergic rhinitis.

Montelukast is also indicated in the prophylaxis of asthma in which the predominant component is exercise-induced bronchoconstriction.

4.2 Posology and method of administration

The dosage for adults 15 years of age and older with asthma, or with asthma and concomitant seasonal allergic rhinitis, is one 10 mg tablet daily to be taken in the evening.

Method of administration:

For oral use.

The tablet should be swallowed with a sufficient amount of fluid (e.g. as glass of water).

General recommendations

The therapeutic effect of montelukast on parameters of asthma control occurs within one day. Montelukast may be taken with or without food. Patients should be advised to continue taking montelukast even if their asthma is under control, as well as during periods of worsening asthma. Montelukast should not be used concomitantly with other products containing the same active ingredient, montelukast.

No dosage adjustment is necessary for the elderly, or 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.

Therapy with montelukast in relation to other treatments for asthma.

Montelukast can be added to a patient's existing treatment regimen.

Inhaled corticosteroids

Treatment with Montelukast can be used as add-on therapy in patients when inhaled corticosteroids plus "as needed" short acting beta-agonists provide inadequate clinical control. Montelukast should not be abruptly substituted for inhaled corticosteroids (see section 4.4).

Other available strengths/ pharmaceutical form:

4    mg chewable tablets are available for paediatric patients 2 to 5 years of age.

5    mg chewable tablets are available for paediatric patients 6 to 14 years of age.

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 beta-agonist should be used. Patients should seek their doctor's advice as soon as possible if they need more inhalations of short-acting beta-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 antiasthma 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 usually, but not always, have been associated with the reduction or withdrawal of oral corticosteroid therapy. The possibility that leukotriene receptor antagonists may be associated with emergence of Churg-Strauss syndrome can neither be excluded nor 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.

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

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, caution should be exercised, particularly in children, when montelukast is co-administered with inducers of CYP 3A4, 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 metabolised by this enzyme (e.g., paclitaxel, rosiglitazone, and repaglinide.)

4.6 Fertility, pregnancy and lactation

Use during pregnancy

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

Limited data from available pregnancy databases do not suggest a causal relationship between montelukast and malformations (i.e. limb defects) that have been rarely reported in worldwide post marketing experience.

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

Use during lactation

Studies in rats have shown that montelukast is excreted in milk (see section 5.3). It is not known if montelukast is excreted in human milk.

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

Fertility See section 5.3.

4.7 Effects on ability to drive and use machines

Montelukast is not expected to affect a patient's ability to drive a car or operate machinery. However, in very rare cases, individuals have reported drowsiness or dizziness.

4.8 Undesirable effects

Montelukast has been evaluated in clinical studies as follows:

•    10 mg film-coated tablets in approximately 4000 adult asthmatic patients 15

years of age and older.

•    10 mg film-coated tablets in approximately 400 adult asthmatic patients with seasonal allergic rhinitis 15 years of age and older.

•    5 mg chewable tablets in approximately 1750 paediatric asthmatic patients 6 to 14 years of age.

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

Body System Class	Adult Patients 15 years	Paediatric Patients 6 to 14
	and older	years old
	(two 12-week studies;	(one 8-week study; n=201)
	n=795)	(two 56-week studies; n=615)
Nervous system disorders	headache	headache
Gastrointestinal disorders	abdominal pain

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.

Post marketing experience:

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

System Organ Class	Adverse Experience Term	Frequency Category*
Infections and infestations	Upper respiratory infectionT	Very Common
Blood and lymphatic system disorders	Increased bleeding tendency	Rare
Immune system disorder	Hypersensitivity reactions including anaphylaxis	Uncommon
Psychiatric disorders	dream abnormalities including nightmares, insomnia, somnambulism, irritability, anxiety, restlessness, agitation including aggressive behaviour or hostility, depression	Uncommon
	tremor	Rare
	hallucinations, suicidal	Very Rare

4.9 Overdose

No specific information is available on the treatment of overdose with montelukast. In chronic asthma studies, montelukast 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.

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 1000 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. 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.

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

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Other systemic drugs for obstructive airway diseases, Leukotriene receptor antagonists

ATC-code: R03D C03

The cysteinyl leukotrienes (LTC4, LTD4, LTE4) are potent inflammatory eicosanoids released from various cells including mast cells and eosinophils. These important proasthmatic mediators bind to cysteinyl leukotriene (CysLT) receptors. The CysLT type-1 (CysLTi) 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 bronchoconstriction, mucous secretion, vascular permeability, and eosinophil recruitment. 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.

Montelukast is an orally active compound which binds with high affinity and selectivity to the CysLT1 receptor. In clinical studies, montelukast inhibits bronchoconstriction due to inhaled LTD₄ at doses as low as 5 mg. Bronchodilation

was observed within 2 hours of oral administration. The bronchodilation effect caused by a beta ^- agonist was additive to that caused by montelukast. Treatment with montelukast inhibited both early- and late “ phase bronchoconstriction due to antigen challenge. Montelukast, compared with placebo, decreased peripheral blood eosinophils in adult and paediatric patients. In a separate study, treatment with montelukast significantly decreased eosinophils in the airways (as measured in sputum) and in peripheral blood while improving clinical asthma control.

In studies in adults, montelukast, 10 mg once daily, compared with placebo, demonstrated significant improvements in morning FEVi (10.4% vs 2.7% change from baseline), AM peak expiratory flow rate (PEFR) (24.5 I ./min vs 3.3 I ./min change from baseline), and significant decrease in total beta-agonist use (^- 26.1% vs -4.6% change from baseline). Improvement in patient-reported daytime and nighttime asthma symptoms scores was significantly better than placebo.

Studies in adults demonstrated the ability of montelukast to add to the clinical effect of inhaled corticosteroid (% change from baseline for inhaled beclometasone plus montelukast vs beclometasone, respectively for FEV₁: 5.43% vs 1.04%; beta-agonist use: -8.70% vs 2.64%). Compared with inhaled beclometasone (200 pg twice daily with a spacer device), montelukast demonstrated a more rapid initial response, although over the 12-week study, beclometasone provided a greater average treatment effect (% change from baseline for montelukast vs beclometasone, respectively for FEVi: 7.49% vs 13.3%; beta “ agonist use: -28.28% vs -43.89%). However, compared with beclometasone, a high percentage of patients treated with montelukast achieved similar clinical responses (e.g., 50% of patients treated with beclometasone achieved an improvement in FEV₁ of approximately 11% or more over baseline while approximately 42% of patients treated with montelukast achieved the same response).

A clinical study was conducted to evaluate montelukast for the symptomatic treatment of seasonal allergic rhinitis in adult asthmatic patients 15 years of age and older with concomitant seasonal allergic rhinitis. In this study, montelukast 10 mg tablets administered once daily demonstrated a statistically significant improvement in the Daily Rhinitis Symptoms score, compared with placebo. The Daily Rhinitis Symptoms score is the average of the Daytime Nasal Symptoms score (mean of nasal congestion, rhinorrhea, sneezing, nasal itching) and the Nighttime Symptoms score (mean of nasal congestion upon awakening, difficulty going to sleep, and nighttime awakenings scores). Global evaluations of allergic rhinitis by patients and physicians were significantly improved, compared with placebo. The evaluation of asthma efficacy was not a primary objective in this study.

In an 8-week study in paediatric patients 6 to 14 years of age, montelukast 5 mg once daily, compared with placebo, significantly improved respiratory function (FEV₁ 8.71% vs 4.16% change from baseline; AM PEFR 27.9 L/min vs 17.8 L/min change from baseline) and decreased "as-needed" beta-agonist use (-11.7% vs +8.2% change from baseline). Significant reduction of exercise-induced bronchoconstriction (EIB) was demonstrated in a 12-week study in adults (maximal fall in FEV₁ 22.33% for montelukast vs 32.40% for placebo; time to recovery to within 5% of baseline FEV₁ 44.22 min vs 60.64 min). This effect was consistent throughout the 12-week study period. Reduction in EIB was also demonstrated in a short term study in paediatric patients (maximal fall in FEV₁ 18.27% vs 26.11%; time to recovery to within 5% of baseline FEV₁ 17.76 min vs 27.98 min). The effect in both studies was demonstrated at the end of the once-daily dosing interval.

In aspirin-sensitive asthmatic patients receiving concomitant inhaled and/or oral corticosteroids, treatment with montelukast, compared with placebo, resulted in significant improvement in asthma control (FEV₁ 8.55% vs -1.74% change from baseline and decrease in total beta-agonist use -27.78% vs 2.09% change from baseline).

5.2 Pharmacokinetic properties

Absorption

Montelukast is rapidly 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 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.

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

In vitro studies using human liver microsomes indicate that cytochrome P450 3A4, 2A6 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. 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), 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, gastro-intestinal 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 5000 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.

PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Core:

Lactose monohydrate Cellulose, microcrystalline (E460) Croscarmellose sodium Hydroxypropyl cellulose (E463) Magnesium stearate (E572)

Coating:

Hydroxy propyl cellulose (E463) Hypromellose 6cP (E464) Titanium dioxide (E171)

Iron oxide yellow (E172) Carnauba wax (E903)

Iron oxide red (E172)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

2 years

In use shelf life for HDPE bottle pack: 30 days

6.4 Special precautions for storage

Store below 25⁰C.

Store in the original package in order to protect from light and moisture.

Nature and contents of container

Polyamide / Aluminium foil / PVC - Aluminium foil blisters

Pack sizes: 7, 10, 14, 20, 28, 30, 49, 50, 56, 60, 84, 90, 98, 100, 140 and 200 tablets

HDPE bottle with polypropylene cap containing silica gel desiccant:

Pack sizes: 30 tablets

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

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

7    MARKETING AUTHORISATION HOLDER

Milpharm Limited

Ares, Odyssey Business Park

West End Road

South Ruislip HA4 6QD

United Kingdom

8    MARKETING AUTHORISATION NUMBER(S)

PL 16363/0255

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

23/04/2012

10    DATE OF REVISION OF THE TEXT

23/04/2012