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PAR Montelukast 10mg tablets UK/H/2392 & 3718/01/DC

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Public Assessment Report

Decentralised Procedure

Montelukast 10mg tablets

(montelukast sodium)

UK/H/2392 & 3718/01/DC UK licence number: PL 20658/0045 & 0041

Torrent Pharma GmbH


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LAY SUMMARY On 22nd November 2010, the MHRA granted Torrent Pharma GmbH Marketing Authorisations (licences) for the medicinal product Montelukast 10mg tablets (PL 20658/0041 and 0045). This is a prescription-only medicine (POM). Montelukast is a leukotriene receptor antagonist that blocks substances called leukotrienes. Leukotrienes cause narrowing and swelling of airways in the lungs and also cause allergy symptoms. By blocking leukotrienes, montelukast improves asthma symptoms, helps to control asthma and improves seasonal allergy symptoms (also known as hay fever or seasonal allergic rhinitis). Asthma is a long-term disease and includes:

• Difficulty breathing caused by narrowed airways. This narrowing of airways worsens and improves in response to various conditions.

• Sensitive airways that react to many things, such as cigarette smoke, pollen, cold air, or exercise.

• Swelling (inflammation) in the lining of the airways. Symptoms of asthma include coughing, wheezing and chest tightness. Seasonal allergies (hay fever or seasonal allergic rhinitis) are an allergic response often caused by airborne pollens from trees, grasses and weeds. The symptoms of seasonal allergies typically may include stuffy, runny, itchy nose; sneezing; and watery, swollen, red, itchy eyes. Montelukast 10mg tablets are prescribed to treat asthma, preventing asthma symptoms during the day and night. Montelukast 10mg tablets are used for the treatment of adolescent and adult patients, from 15 years of age, who are not adequately controlled on their medication and need additional therapy. Montelukast 10mg tablets also help prevent the narrowing of airways triggered by exercise. In those asthmatic patients in whom Montelukast 10mg tablets are indicated in asthma, the medicine can also provide symptomatic relief of seasonal allergic rhinitis. No new or unexpected safety concerns arose from these applications and it was, therefore, judged that the benefits of Montelukast 10mg tablets outweigh the risks; hence Marketing Authorisations have been granted.


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TABLE OF CONTENTS

Module 1: Information about initial procedure Page 4 Module 2: Summaries of Product Characteristics Page 5 Module 3: Product Information Leaflets Page 12 Module 4: Labelling Page 20 Module 5: Scientific discussion during initial procedure Page 25 I Introduction Page 25 II About the product Page 27 III Scientific Overview and discussion Page 28 III.1 Quality aspects Page 28 III.2 Non-clinical aspects 2 III.3 Clinical aspects Page 32 IV Overall conclusions and benefit-risk assessment Page 35 Module 6: Steps taken after initial procedure Page 36


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Module 1

Information about Initial Procedure

Product Name


Type of Application

Generic, Article 10.1

Active Substance

Montelukast sodium

Form

Tablets

Strength

10mg

MA Holder

Torrent Pharma GmbH Südwestpark 50 90449 Nürnberg Germany

Reference Member State (RMS)

UK

Concerned Member States (CMS)

UK/H/2392/01/DC: Germany, Italy, Lithuania, Latvia, Poland, Portugal, Romania and Spain

UK/H/3718/01/DC: Czech Republic, Denmark, Estonia, Finland, Hungary, Lithuania, Latvia, Norway, Poland, Sweden and Slovakia

Procedure Number

UK/H/2392 & 3718/01/DC

Timetable

End of Procedure: Day 210 – 13th October 2010


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Module 2

Summary of Product Characteristics

The UK Summary of Product Characteristics (SmPC) for Montelukast 10mg tablets (PL 20658/0041 and 0045) is as follows. Differences between the individual SmPCs are highlighted: 1 NAME OF THE MEDICINAL PRODUCT

Montelukast 10 mg tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 10.4 mg montelukast sodium which corresponds to 10 mg montelukast. Excipients: Aspartame 0.75 mg per tablet For a full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Tablet Light brown coloured, round biconvex shaped, uncoated tablet, with breakline on both sides. The tablet can be divided into equal halves.

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 β-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 and adolescents 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. Montelukast tablets may be taken with or without food. Method of administration: For oral use. The tablet should be swallowed with a sufficient amount of fluid (e.g. a glass of water). 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. 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 β- agonists provide inadequate clinical control. Montelukast should not be substituted for inhaled corticosteroids (see section 4.4).


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Other available strengths/pharmaceuticals 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.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients.

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 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 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 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 medicinal products. Montelukast 10 mg tablets contain aspartame, a source of phenylalanine. May be harmful for patients with phenylketonuria. Each 10 mg tablet contains phenylalanine in an amount equivalent to 0.421 mg phenylalanine per dose.

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 coadministered 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 metabolized by this enzyme (e.g., paclitaxel, rosiglitazone, and repaglinide).

4.6 Pregnancy and lactation

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


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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 mothers only if it is considered to be clearly essential.

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 tablets in approximately 4,000 adults and adolescent patients 15 years of age and older.

• 10 mg tablets in approximately 400 adult and adolescent patients from 15 years of age and older with seasonal allergic rhinitis.

• 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.

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 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)

Nervous system disorders headache headache

Gastro-intestinal 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. The following adverse reactions have been reported in post-marketing use:

Infections and infestations: upper respiratory infection.

Blood and lymphatic system disorders: increased bleeding tendency.

Immune system disorders: hypersensitivity reactions including anaphylaxis, hepatic eosinophilic infiltration.

Psychiatric disorders: dream abnormalities including nightmares, hallucinations, insomnia, somnambulism, irritability, anxiety, restlessness, agitation including aggressive behaviour or hostility, tremor, depression, suicidal thinking and behaviour (suicidality) in very rare cases.

Nervous system disorders: dizziness, drowsiness, paraesthesia/hypoesthesia, seizure.

Cardiac disorders: palpitations.

Respiratory, thoracic and mediastinal disorders: epistaxis.

Gastrointestinal disorders: diarrhoea, dry mouth, dyspepsia, nausea, vomiting.


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Hepatobiliary disorders: elevated levels of serum transaminases (ALT, AST), hepatitis (including cholestatic, hepatocellular, and mixed-pattern liver injury).

Skin and subcutaneous tissue disorders: angiooedema, bruising, urticaria, pruritus, rash, erythema nodosum.

Musculoskeletal and connective tissue disorders: arthralgia, myalgia including muscle cramps.

General disorders and administration site conditions: asthenia/fatigue, malaise, oedema, pyrexia.

Very rare cases of Churg-Strauss Syndrome (CSS) have been reported during montelukast treatment in asthmatic patients (see section 4.4).

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 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 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 dialyzable by peritoneal- or hemo-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 pro-asthmatic mediators bind to cysteinyl leukotriene (CysLT) receptors. The CysLT type-1 (CysLT1) 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 β-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 FEV1 (10.4% vs 2.7% change from baseline), AM peak expiratory flow rate (PEFR) (24.5 L/min vs 3.3 L/min change from baseline), and significant decrease in total β-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.


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Studies in adults demonstrated the ability of montelukast to add to the clinical effect of inhaled corticosteroid (% change from baseline for inhaled beclomethasone plus montelukast vs beclomethasone, respectively for FEV1: 5.43% vs 1.04%; β-agonist use: -8.70% vs 2.64%). Compared with inhaled beclomethasone (200 μg twice daily with a spacer device), montelukast demonstrated a more rapid initial response, although over the 12-week study, beclomethasone provided a greater average treatment effect (% change from baseline for montelukast vs beclomethasone, respectively for FEV1: 7.49% vs 13.3%; β-agonist use: -28.28% vs -43.89%). However, compared with beclomethasone, a high percentage of patients treated with montelukast achieved similar clinical responses (e.g., 50% of patients treated with beclomethasone 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" β-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 6 to 14 years of age (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 β-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 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 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. Distribution. Montelukast is more than 99% bound to plasma proteins. The steady-state volume of distribution of montelukast averages 8-11 liters. Studies in rats with radiolabeled montelukast indicate minimal distribution across the blood-brain barrier. In addition, concentrations of radiolabeled 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. 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


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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 radiolabeled montelukast, 86% of the radioactivity was recovered in 5-day fecal 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 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.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Mannitol (E421) Cellulose, Microcrystalline Croscarmellose Sodium Magnesium Stearate Aspartame (E951) Cherry Flavour (Firmenich CHERRY 501027 AP0551) Iron oxide yellow (E172) Iron Oxide Red (E172)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years


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6.4 Special precautions for storage

This medicinal product does not require any special temperature storage conditions. Store in the original package in order to protect from light and moisture.

6.5 Nature and contents of container

Tablets are packed into a cold forming blister foil sealed with aluminium foil (Alu/Alu blister). The blisters are packed into cartons. For PL 20658/0041: Pack sizes of: 28, 56, 98 tablets For PL 20658/0045: Pack sizes of: 10, 14, 20, 28, 50, 56, 98, 100 tablets Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements. Any unused product or waste material should be disposed of in accordance with local requirements.

7 MARKETING AUTHORISATION HOLDER


8 MARKETING AUTHORISATION NUMBER(S)

PL 20658/0041 PL 20658/0045

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

22/11/2010 10 DATE OF REVISION OF THE TEXT

22/11/2010


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Module 3

Patient Information Leaflet (PIL)

Montelukast 10mg tablets - PL 20658/0041 - text version


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Montelukast 10mg tablets - PL 20658/0045 - mock up PIL


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Module 4

Labelling text

Montelukast 10mg tablets - PL 20658/0041 - labelling text


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Montelukast 10mg tablets - PL 20658/0045 - labelling mock up

Carton

Braille


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Blister foil


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Module 5

Scientific discussion during initial procedure I INTRODUCTION Based on the review of the data on quality, safety and efficacy, the MHRA granted Torrent Pharma GmbH Marketing Authorisations for the medicinal product Montelukast 10mg tablets (20658/0045 and 0041; UK/H/2392 & 3718/01/DC) on 22nd November 2010. The product is a prescription-only medicine. These are generic applications for Montelukast 10mg tablets, submitted under Article 10.1 of 2001/83 EC, as amended. The applications refer to the UK reference product, Singulair 10mg film-coated tablets (PL 00025/0358), authorised to Merck Sharp & Dohme Limited on 15th January 1998, through an incoming Mutual Recognition procedure where Finland was the Reference Member State (RMS). The European originator product is Singulair 10mg, film-coated tablet, authorised to Merck Sharp & Dohme Ltd in Finland on 25th August 1997. The UK reference product has been authorised in the UK for more than 10 years, thus the period of data exclusivity has expired. Montelukast 10mg tablets are 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 β-2-agonists provide inadequate clinical control of asthma. In those asthmatic patients in whom Montelukast 10mg tablets are indicated in asthma, this medicine can also provide symptomatic relief of seasonal allergic rhinitis. Montelukast 10mg tablets are also indicated in the prophylaxis of asthma in which the predominant component is exercise-induced bronchoconstriction. The active ingredient, montelukast (present as the sodium salt) belongs to the pharmacotherapeutic group, 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 pro-asthmatic mediators bind to cysteinyl leukotriene receptors (CysLT). The CysLT type-1 (CysLT1) 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. No new non-clinical or clinical efficacy studies were conducted for these applications, which is acceptable given that the applications were for a generic version of a product that has been licensed for over 10 years.


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The applications are supported by the bioequivalence study presented by the applicant comparing the pharmacokinetic profile of the test product, Montelukast 10mg tablets, to that of the reference product, Singulair 10mg Filmtabletten (Merck Sharp & Dohme, Germany). The bioequivalence study was carried out in accordance with Good Clinical Practice (GCP). The RMS has been assured that acceptable standards of Good Manufacturing Practice (GMP) are in place for this product type at all sites responsible for the manufacture and assembly of these products. Evidence of compliance with GMP has been provided for the named manufacturing and assembly sites. For manufacturing sites within the Community, the RMS has accepted copies of current manufacturer authorisations issued by inspection services of the competent authorities as certification that acceptable standards of GMP are in place at those sites. For manufacturing sites outside the community, the RMS has accepted copies of current GMP Certificates or satisfactory inspection summary reports, ‘close-out letters’ or ‘exchange of information’ issued by the inspection services of the competent authorities (or those countries with which the EEA has a Mutual Recognition Agreement for their own territories) as certification that acceptable standards of GMP are in place at those non-Community sites. The RMS considers that the pharmacovigilance system as described by the Marketing Authorisation Holder (MAH) fulfils the requirements and provides adequate evidence that the MAH has the services of a Qualified Person (QP) responsible for pharmacovigilance and has the necessary means for the notification of any adverse reaction suspected of occurring either in the Community or in a third country. The Marketing Authorisation Holder has provided adequate justification for not submitting a Risk Management Plan (RMP). As the applications are for a generic version of an already authorised reference product, for which safety concerns requiring additional risk minimisation have not been identified, routine pharmacovigilance activities are proposed and a risk minimisation system is not considered necessary. The reference product has been in use for many years and the safety profile of the active is well-established. The Marketing Authorisation Holder has provided adequate justification for not submitting an Environmental Risk Assessment (ERA). These were applications for a generic product and there is no reason to conclude that marketing of this product will change the overall use pattern of the existing market. There are no environmental concerns associated with the method of manufacture or formulation of the product.


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II. ABOUT THE PRODUCT Name of the product in the Reference Member State


Name(s) of the active substance(s) (INN)

Montelukast sodium

Pharmacotherapeutic classification (ATC code)

Leukotriene receptor antagonists (RO3D CO3)

Pharmaceutical form and strength(s)

Tablets 10mg

Reference numbers for the Mutual Recognition Procedure

UK/H/2392 & 3718/01/DC

Reference Member State

United Kingdom

Member States concerned

UK/H/2392/01/DC: Germany, Italy, Lithuania, Latvia, Poland, Portugal, Romania and Spain

UK/H/3718/01/DC: Czech Republic, Denmark, Estonia, Finland, Hungary, Lithuania, Latvia, Norway, Poland, Sweden and Slovakia

Marketing Authorisation Number(s)

PL 20658/0041 and 0045

Name and address of the authorisation holder



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III SCIENTIFIC OVERVIEW AND DISCUSSION

III.1 QUALITY ASPECTS

ACTIVE SUBSTANCE

Montelukast sodium

Nomenclature:

INN: Montelukast sodium

Chemical names: i) [R-(E)]-1-[[[1-[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(1-hydroxy-1methylethyl)phenyl]propyl]thio]methyl]cyclopropaneacetic acid, monosodium salt

ii) Sodium salt of 1-[[[(1R)-1-[3-[(1E)-2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl]thio]methyl]cyclopropane acetic acid

Structure:

Molecular formula: C35H35ClNNaO3S

Molecular weight: 608.18 g/mol

CAS No: 151767-02-1

Physical form: A white to off-white amorphous powder, hygroscopic in nature

Solubility: Soluble in methanol and water, practically insoluble in acetonitrile

Polymorphism: A crystalline and an amorphous form are known. The active substance, montelukast sodium, is not the subject of a European Pharmacopeia (Ph. Eur.) or British Pharmacopeia (B.P.) monograph. Synthesis of the active substance from the designated starting materials has been adequately described and appropriate in-process controls and intermediate specifications are applied. Satisfactory specifications are in place for all starting materials and reagents and these are supported by relevant Certificates of Analysis. Confirmation has been provided that the raw materials, intermediates and auxiliary agents used in synthesis of the active are not of animal, biological or genetically modified origin. Appropriate specifications have been provided for the active substance. Analytical methods have been appropriately validated and are satisfactory for ensuring compliance with the relevant specifications. Batch analysis data are provided and comply with the proposed specifications. Satisfactory Certificates of Analysis have been provided for any reference standards used by the active substance manufacturer during validation studies. The active substance is stored in appropriate packaging. It is packed in double low-density polyethylene (LDPE) bags (clear-black), inside a triple laminated bag. This is placed inside another triple laminated bag. All bags are purged with nitrogen and contain silica gel bags. The bag is placed inside a high-density polyethylene (HDPE) container with HDPE lid. Specifications and Certificates of Analysis have been provided for the packaging materials


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used. The primary packaging in direct contact with the active substance satisfies Directive 2002/72/EC (as amended), and is suitable for contact with foodstuffs. Appropriate stability data have been generated by the active substance manufacturer for active substance stored in the proposed commercial packaging. Based on the data, a retest period of 24 months has been set, when stored protected from air and light at no more than 25°C (15-30°C); this is satisfactory. MEDICINAL PRODUCT

Description and Composition

Montelukast 10mg tablets contain 10mg of the active ingredient, montelukast, as montelukast sodium, and are presented as light brown coloured, round biconvex shaped, uncoated tablets, with a breakline on both sides. The tablets can be divided into equal halves. Other ingredients consist of pharmaceutical excipients, namely mannitol (E421), microcrystalline cellulose, croscarmellose sodium, magnesium stearate, aspartame (E951), cherry flavour (Firmenich CHERRY 501027 AP0551), iron oxide yellow (E172), and iron oxide red (E172). Appropriate justification for the inclusion of each excipient has been provided. All excipients used comply with their respective European Pharmacopoeia monographs, with the exception of cherry flavour, which complies with satisfactory in-house specifications, and the colourants, iron oxide yellow (E172) and iron oxide red (E172), which comply with the requirements of the United States Pharmacopoeia National Formulary. It is stated that iron oxide yellow and iron oxide red comply with the EU food colouring regulation 95/45/EC. Satisfactory Certificates of Analysis have been provided for all excipients. The magnesium stearate has been confirmed as being of vegetable origin. The applicant has provided a declaration confirming that there are no materials of human or animal origin contained in or used in the manufacturing process for the proposed product. None of the excipients are sourced from genetically modified organisms. There were no novel excipients used and no overages. Pharmaceutical development

Details of the pharmaceutical development of the medicinal product have been supplied and are satisfactory. The aim was to develop a generic medicinal product bioequivalent to the reference product, Singulair 10mg film-coated tablets (PL 00025/0358, Merck Sharp & Dohme Limited). Comparative dissolution and impurity data were provided for batches of the test product and appropriate reference products. The dissolution and impurity profiles were satisfactory. Manufacture

A description and flow-chart of the manufacturing method has been provided. In-process controls are appropriate considering the nature of the product and the method of manufacture. Process validation studies were conducted and the results were satisfactory. An appropriate scheme for further process validation has been submitted.


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Finished product specification

The finished product specifications are provided for both release and shelf-life and are satisfactory. Acceptance limits have been justified with respect to conventional pharmaceutical requirements and, where appropriate, safety. Test methods have been described and have been adequately validated, as appropriate. Satisfactory batch analysis data are provided and accepted. Certificates of Analysis have been provided for any reference standards used. Container Closure System

The finished product is licensed for marketing in cold-forming blister foils sealed with aluminium foil to give aluminium- aluminium blisters. The blisters are packaged with the Patient Information Leaflet (PIL) into cardboard outer cartons in pack sizes of 10, 14, 20, 28, 50, 56, 98 and 100 coated tablets (pack sizes for PL 20658/0041 are 28, 56 and 98 only). The MAH has stated that not all pack sizes may be marketed. Satisfactory specifications and Certificates of Analysis for all packaging components used have been provided. All primary product packaging complies with EU legislation, Directive 2002/72/EC (as amended), and is suitable for contact with foodstuffs. Stability

Finished product stability studies have been conducted in accordance with current guidelines, using product stored in the packaging proposed for marketing. Based on the results, a shelf-life of 3 years has been set, which is satisfactory. Storage instructions are ‘Store in the original package in order to protect from light and moisture’. Bioequivalence Study

A bioequivalence study was presented comparing the test product, Montelukast 10mg tablets, to the reference product, Singulair 10mg Filmtabletten (Merck Sharp & Dohme, Germany). An evaluation of the bioequivalence study is found in the Clinical Aspects section. Quality Overall Summary

A satisfactory quality overview is provided, and has been prepared by an appropriately qualified expert. The CV of the expert has been supplied. Product Information

The approved Summaries of Product Characteristics (SmPCs), and Patient Information Leaflet (PIL) and labelling texts are satisfactory. The user testing of the PIL text has been evaluated and is accepted. The labelling fulfils the statutory requirements for Braille. For PL 20658/0041, the MAH has submitted text versions only and has committed to submitting mock-up livery to the relevant regulatory authorities for approval before packs are marketed. For PL 20658/0045, satisfactory mock-ups of the PIL and labelling have been provided. PIL user testing has been accepted, based on a bridging report provided by the applicant making reference to the successful user-testing of the PIL for Montelukast 5mg chewable tablets (PL 20658/0043; UK/H/3719/02/DC). Differences between the ‘Daughter’


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(Montelukast 10mg tablets) and ‘Parent’ (Montelukast 5mg chewable tablets) leaflets were presented and analysed and it was shown that the differences have no material impact on readability. Therefore, results from the readability testing study of the Parent PIL can be extrapolated to the Daughter PIL and the bridging is accepted. The MAH has stated that not all licensed pack sizes may be marketed. They have committed to submitting mock-ups for unmarketed pack sizes to the relevant regulatory authorities for approval before those packs are commercially marketed. Conclusion

All pharmaceutical issues have been resolved and the quality grounds for these applications are considered adequate. There are no objections to approval of Montelukast 10mg tablets from a pharmaceutical point of view.


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III.2 NON-CLINICAL ASPECTS Specific non-clinical studies have not been performed, which is acceptable considering that these are applications for a generic version of a product that has been licensed for more than 10 years. The non-clinical overview provides a satisfactory review of the pharmacodynamic, pharmacokinetic, and toxicological properties of montelukast sodium, a widely used and well-known active substance. The overview, dated October 2007, cites 23 references from the published literature dated up to year 2006. The CV of the non-clinical expert has been supplied. For generic applications of this nature, the need for repetitive tests on animals and humans is avoided. Reference is made to the UK reference product, Singulair 10mg film-coated tablet (Merck Sharp & Dohme Limited). There are no objections to approval of Montelukast 10mg tablets from a non-clinical point of view. III.3 CLINICAL ASPECTS 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 β-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. The indications are consistent with those for the reference product and are satisfactory. POSOLOGY AND METHOD OF ADMINISTRATION The dosage for patients 15 years of age and older with asthma, or with asthma and concomitant seasonal allergic rhinitis, is one 10mg tablet daily, to be taken in the evening, with or without food. The therapeutic effect of this medicine on parameters of asthma control occurs within one day. Full details concerning the posology are provided in the SmPCs. The posology is consistent with that for the UK reference product and is satisfactory. TOXICOLOGY The toxicology of montelukast sodium is well known. No new data have been submitted and none are required for applications of this type. CLINICAL PHARMACOLOGY The clinical pharmacology of montelukast sodium is well known. With the exception of the bioequivalence study, no new pharmacodynamic or pharmacokinetic data are supplied and none are required for these applications. Pharmacokinetics – bioequivalence study The applications are supported by the bioequivalence study presented by the applicant comparing the pharmacokinetic profiles of Montelukast 10mg coated tablets (test) and Singulair 10mg Filmtabletten - Merck Sharp & Dohme, Germany (reference). The study was of an appropriate design and was conducted to principles of Good Clinical Practice (GCP).


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This was a comparative, randomised, open-label, single-dose, 2-period, crossover, bioequivalence study conducted in 28 healthy adult human subjects under fasting conditions. A single dose of the investigational products was administered orally, with 240 ml of water, to each subject in each period. A satisfactory washout period of 7 days was maintained between the two dosing days in each group. Blood samples were taken pre-dose (0.0) and at specified time points up to 24.0 hours after administration of test or reference product. Plasma levels of montelukast were detected by a validated HPLC analytical method. The primary pharmacokinetic parameters for this study were Cmax and AUC0-t. Bioequivalence of the test product versus the reference product was concluded if the 90% Confidence Intervals (CI) fell within the acceptance range, 0.80-1.25 (80.00%-125.00%), for log-transformed Cmax and AUC0-t. Results:

28 subjects were enrolled in the study; 24 of these completed the study and were included in the pharmacokinetic evaluation and statistical analysis. The discontinuation, and non-inclusion in the pharmacokinetic analysis, of 4 subjects was satisfactorily justified. Safety – A total of 6 non-serious adverse events (AEs) were registered in 5 volunteers in the course of the trial - 2 AEs occurred after administration of the test product; 1 AE occurred before any dosing; 3 AEs occurred after administration of the reference drug. The results of laboratory screening gave no indications for adverse events or adverse drug reactions. There were no deaths or serious or significant adverse events. The summary of the results of the bioequivalence study are tabulated below: Pharmacokinetic results for montekulast for a randomised, open-label, 2-period, single-dose crossover study between the 10mg strength test and reference products. n=24 healthy subjects, dosed fasted; t=24 hours. Wash-out period: 7 days

Geometric Least Squares Mean Parameters

Reference Product (X)

Test Product (Y)

Ratio (Y/X) %

90% CI

(Parametric)

Cmax (ng/ml) 487.33 554.25 1.119 102.5-122.3%

AUC0-t (ng.h/ml) 3138.56 3448.54 1.092 102.1-116.7%

AUC0-t area under the plasma concentration-time curve from time zero to t hours Cmax maximum plasma concentration

Conclusion on Bioequivalence

The results of the bioequivalence study show that the test and reference products are bioequivalent, under fasting conditions, as the confidence intervals for Cmax and AUC0-t for montelukast fall within the acceptance criteria ranges of 80.00-125.00%, in line with current guidelines.


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Clinical efficacy

No new data have been submitted and none are required. The UK reference product is established and the applications depend upon the ability to demonstrate bioequivalence. Efficacy is reviewed in the clinical overview. The efficacy of montelukast sodium is well-established from its extensive use in clinical practice. Clinical safety

No new data have been submitted and none are required for applications of this type. No new or unexpected safety concerns arose from these applications. Safety is reviewed in the clinical overview. The safety profile of montelukast sodium is well-known. PRODUCT INFORMATION:

Summary of Product Characteristics (SmPC)

The approved SmPCs are consistent with that for the UK reference product and are acceptable. Patient Information Leaflet

The final PIL text is in line with the approved SmPCs and is satisfactory. The PIL user testing has been evaluated and is accepted. Labelling

The labelling text is satisfactory. Clinical overview

A satisfactory clinical overview is provided, and has been prepared by an appropriately qualified expert. The overview cites 31 publications up to year 2006. The CV of the clinical expert has been supplied. CONCLUSIONS For generic applications of this nature, the need for repetitive tests on animals and humans is avoided. Reference is made to the UK reference product, Singulair 10mg film-coated tablet (Merck Sharp & Dohme Limited). Sufficient clinical information has been submitted to support these applications. The risk-benefit of the product is considered favourable from a clinical perspective. The grant of Marketing Authorisations was, therefore, recommended on medical grounds.


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IV OVERALL CONCLUSION AND BENEFIT-RISK ASSESSMENT QUALITY

The important quality characteristics of Montelukast 10mg tablets are well-defined and controlled. The specifications and batch analytical results indicate consistency from batch to batch. There are no outstanding quality issues that would have a negative impact on the benefit/risk balance. NON-CLINICAL

No new non-clinical data were submitted and none are required for applications of this type. EFFICACY

Bioequivalence has been demonstrated between the applicant’s Montelukast 10mg tablets, and the reference product, Singulair 10mg Filmtabletten (Merck Sharp & Dohme, Germany). No new or unexpected safety concerns arise from these applications. PRODUCT LITERATURE

The approved SmPCs are consistent with that for the UK reference product and are satisfactory. The approved Patient Information Leaflet (PIL) and labelling texts are satisfactory. The labelling fulfils the statutory requirements for Braille. For PL 20658/0041, the MAH has submitted text versions only and has committed to submitting mock-up livery to the relevant regulatory authorities for approval before packs are marketed. For PL 20658/0045, satisfactory mock-ups of the PIL and labelling have been provided. The approved labelling artwork complies with statutory requirements. In line with current legislation, the name of the product in Braille appears on the outer packaging and sufficient space has been included for a standard UK pharmacy dispensing label. PIL user testing has been accepted, based on a bridging report provided by the applicant making reference to the successful user-testing of the PIL for Montelukast 5mg chewable tablets (PL 20658/0043; UK/H/3719/02/DC). The bridging report is accepted. The MAH has stated that not all licensed pack sizes may be marketed. They have committed to submitting mock-ups for unmarketed pack sizes to the relevant regulatory authorities for approval before those packs are commercially marketed. BENEFIT-RISK ASSESSMENT

The quality of the product is acceptable and no new non-clinical or clinical safety concerns have been identified. The bioequivalence study and its conclusions support the claim that the applicant’s product, Montelukast 10mg tablets, and the reference product, Singulair 10mg film-coated tablets (Merck Sharp & Dohme Limited), are interchangeable. Extensive clinical experience with montelukast sodium is considered to have demonstrated the therapeutic value of the active substance. The benefit: risk ratio is considered to be positive.


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Module 6

STEPS TAKEN AFTER INITIAL PROCEDURE - SUMMARY Date submitted

Application type

Scope Outcome

public assessment report decentralised procedure - · pdf filepar montelukast 10mg tablets...

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