Montelukast Tablet - MSD

PAR Montelukast 10mg film-coated tablets UK/H/2576-84/03/DC
Public Assessment Report
Decentralised Procedure
Montelukast 10mg film-coated tablets
(montelukast sodium)
UK/H/2576-84/03/DC
UK licence number: PL 20897/0008, 0011, 0014,
0017, 0020, 0023, 0026, 0029, 0032
Helm AG
1
LAY SUMMARY
On 3rd September 2010, the MHRA granted Helm AG Marketing Authorisations (licences)
for the medicinal product Montelukast 10mg film-coated tablets (PL 20897/0008, 0011,
0014, 0017, 0020, 0023, 0026, 0029 and 0032). 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 film-coated tablets are prescribed to treat asthma, preventing asthma
symptoms during the day and night. Montelukast 10mg film-coated 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 film-coated
tablets also help prevent the narrowing of airways triggered by exercise. In those asthmatic
patients in whom Montelukast 10mg film-coated tablets is 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 film-coated tablets outweigh the risks; hence
Marketing Authorisations have been granted.
2
TABLE OF CONTENTS
Module 1: Information about initial procedure Page 4
Module 2: Summaries of Product Characteristics Page 5
Module 3: Product Information Leaflet Page 12
Module 4: Labelling Page 17
Module 5: Scientific discussion during initial procedure Page 19
I Introduction Page 19
II About the product Page 21
III Scientific Overview and discussion Page 22
III.1 Quality aspects Page 22
III.2 Non-clinical aspects Page 25
III.3 Clinical aspects Page 25
IV Overall conclusions and benefit-risk assessment Page 28
Module 6: Steps taken after initial procedure Page 29
3
Module 1
Information about Initial Procedure
Product Name Montelukast 10mg film-coated tablets
Type of Application Generic, Article 10.1
Active Substance Montelukast sodium
Form Film-coated tablets
Strength 10mg
MA Holder Helm AG
Nordkanalstrasse 28, 20097 Hamburg
Germany
Reference Member State UK

(RMS)
Concerned Member UK/H/2576/03/DC: Denmark, Finland, Norway, Sweden

States (CMS)
UK/H/2577/03/DC: Bulgaria, Czech Republic, Estonia,
Hungary, Lithuania, Latvia, Poland, Romania, Slovakia
UK/H/2578/03/DC: Bulgaria, Czech Republic, Hungary, Poland,
Romania, Slovakia
UK/H/2579/03/DC: Finland
UK/H/2580/03/DC: Austria, Germany, Poland
UK/H/2581/03/DC: Belgium, Luxembourg, Netherlands
UK/H/2582/03/DC: Germany
UK/H/2583/03/DC: Austria, Germany, Italy
UK/H/2584/03/DC: Cyprus, Greece
Procedure Number UK/H/2576-84/03/DC
Timetable End of Procedure: Day 210 1st July 2010
4
Module 2
Summary of Product Characteristics
PL 20897/0008, 0011, 0014, 0017, 0020, 0023, 0026, 0029 and 0032
1 NAME OF THE MEDICINAL PRODUCT

Montelukast 10 mg film-coated tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION

One film-coated tablet contains montelukast sodium, which is equivalent to 10 mg montelukast.
Excipient: Lactose monohydrate 89.6 mg per tablet
For a full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Film-coated tablet.
Square, biconvex, beige tablets, MOK 10 engraved on one side and PHD471 on the other.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Montelukast is indicated in the treatment of asthma as add-on therapy in those patients with mild to
moderate persistent asthma who are inadequately controlled on inhaled corticosteroids and in whom
as-needed short acting -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.
Montelukast is indicated in adults from 15 years of age.
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.
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 -agonists provide inadequate clinical control.
Montelukast should not be substituted for inhaled corticosteroids (see section 4.4).
5
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 -agonist should be used. Patients should seek their doctors' advice as soon as
possible if they need more inhalations of short-acting -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 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 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.
6
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 into milk (see section 5.3). It is not known if
montelukast is excreted in human milk.
Montelukast may be used during in breast-feeding 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 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,
<1/10) in asthmatic patients treated with montelukast and at a greater incidence than in patients treated
with placebo:
Body System Class Adult patients Paediatric patients

15 years and older 6 to 14 years old
(two 12-week studies; n=795) (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.
Gastro-intestinal disorders: diarrhoea, dry mouth, dyspepsia, nausea, vomiting.
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.
7
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 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 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 -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 -agonist use
(-26.1% vs -4.6% change from baseline). Improvement in patient-reported daytime and night time
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%; -agonist use: -8.70% vs 2.64%). Compared with inhaled
beclometasone (200 g twice daily with a spacer device), montelukast demonstrated a more rapid
8
initial response, although over the 12-week study, beclometasone provided a greater average treatment
effect (% change from baseline for montelukast vs beclometasone, respectively for FEV1: 7.49% vs
13.3%; -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" -
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 -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 (Cmax) is achieved 3 hours (Tmax) after administration in adults in the
fasted state. The mean oral bioavailability is 64%. The oral bioavailability and Cmax are not influenced
by a standard meal. Safety and efficacy were demonstrated in clinical trials where the 10 mg film-
coated tablet was administered without regard to the timing of food ingestion.
For the 5 mg chewable tablet, the Cmax is achieved in 2 hours after administration in adults in the fasted
state. The mean oral bioavailability is 73% and is decreased to 63% by a standard meal.
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.
9
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.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Cellulose, microcrystalline
Lactose monohydrate
Croscarmellose sodium
Low-Substituted Hydroxypropyl-cellulose (E463)
Magnesium stearate
Film coating:
Opadry Orange:
Iron oxide black (E172)
Hypromellose
Iron Oxide red (E172)
Macrogol
Titanium Dioxide (E171)
Iron Oxide yellow (E172)
Macrogol (6000)
6.2 Incompatibilities
Not applicable.
10
6.3 Shelf life

2 years
6.4 Special precautions for storage

Do not store above 30C.
Store in original package in order to protect from light and moisture.
6.5 Nature and contents of container

Packaged in polyamide/PVC/aluminium blister packed in cardboard boxes..
Pack sizes of 14, 20, 28, 30, 50, 98 and 100 film-coated 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

Helm AG
Germany
8 MARKETING AUTHORISATION NUMBER(S)

PL 20897/0008
PL 20897/0011
PL 20897/0014
PL 20897/0017
PL 20897/0020
PL 20897/0023
PL 20897/0026
PL 20897/0029
PL 20897/0032
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

03/09/2010
10 DATE OF REVISION OF THE TEXT

03/09/2010
11
Module 3
Patient Information Leaflet text
PL 20897/0008, 0011, 0014, 0017, 0020, 0023, 0026, 0029 and 0032
12
13
14
15
16
Module 4
Labelling text
PL 20897/0008, 0011, 0014, 0017, 0020, 0023, 0026, 0029 and 0032
17
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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 Helm AG
Marketing Authorisations for the medicinal product Montelukast 10mg film-coated tablets
(PL 20897/0008, 0011, 0014, 0017, 0020, 0023, 0026, 0029 and 0032; UK/H/2576-
84/03/DC) on 3rd September 2010. The product is a prescription-only medicine.
These are generic applications for Montelukast 10mg film-coated 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 film-coated tablets are indicated in patients from 15 years of age.
Montelukast 10mg film-coated tablets are indicated in the treatment of asthma as add-on
therapy in those patients with mild to moderate, persistent asthma who are inadequately
controlled on inhaled corticosteroids and in whom as-needed short acting -2-agonists
provide inadequate clinical control of asthma.
In those asthmatic patients in whom Montelukast 10mg film-coated tablets is indicated in

asthma, this medicine can also provide symptomatic relief of seasonal allergic rhinitis.
Montelukast 10mg film-coated 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.
19
The applications are supported by the single bioequivalence study presented by the applicant
comparing the pharmacokinetic profile of the test product, Montelukast 10mg film-coated
tablets, to that of the reference product, Singulair 10mg film-coated tablets (Merck Sharp &
Dohme Limited). 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, 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.
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II. ABOUT THE PRODUCT
Name of the product in the Reference Member Montelukast 10mg film-coated tablets
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) Film-coated tablets

10mg
Reference numbers for the Mutual Recognition UK/H/2576-84/03/DC

Procedure
Reference Member State United Kingdom
Member States concerned UK/H/2576/03/DC: DK, FI, NO, SE

UK/H/2577/03/DC: BG, CZ, EE, HU, LT,
LV, PL, RO, SK
UK/H/2578/03/DC: BG, CZ, HU, PL, RO,
SK
UK/H/2579/03/DC: FI
UK/H/2580/03/DC: AT, DE, PL
UK/H/2581/03/DC: BE, LU, NL
UK/H/2582/03/DC: DE
UK/H/2583/03/DC: AT, DE, IT
UK/H/2584/03/DC: CY, EL
Marketing Authorisation Number(s) PL 20897/0008, 0011, 0014, 0017, 0020,

0023, 0026, 0029 and 0032
Name and address of the authorisation holder Helm AG

Germany
21
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 manufacturers during validation studies.
The active substance is stored in appropriate packaging. Specifications and Certificates of

Analysis have been provided for the packaging materials 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.
22
Appropriate stability data have been generated by both active substance manufacturers for
active substance stored in the proposed commercial packaging. These data demonstrate the
stability of the active substance and appropriate retest periods have been applied.
MEDICINAL PRODUCT
Description and Composition
Montelukast 10mg film-coated tablets are presented as square, biconvex, beige, film-coated
tablets, engraved with MOK 10 on one side and PHD471 on the other side. The tablets
contain 10mg of the active ingredient, montelukast, as montelukast sodium.
Other ingredients consist of pharmaceutical excipients, namely microcrystalline cellulose,

lactose monohydrate, croscarmellose sodium, low-substituted hydroxypropylcellulose (E463)
and magnesium stearate making up the tablet core; and Opadry Orange 03B23378 and
macrogol 6000 making up the film coating. Opadry Orange 03B23378 consists of
hypromellose, macrogol, titanium dioxide (E171), iron oxide yellow (E172), iron oxide red
(E172) and iron oxide black (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 low-substituted hydroxypropylcellulose (E463), which meets the
requirements of the NF; and Opadry Orange 03B23378, which complies with satisfactory in-
house specifications. Satisfactory Certificates of Analysis have been provided for all
excipients.
The magnesium stearate has been confirmed as being of vegetable origin. The only excipient
used that contains material of animal or human origin is lactose monohydrate. The applicant
has provided a declaration that milk used in the production of lactose monohydrate is sourced
from healthy animals under the same conditions as that for human consumption. 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 medicinal product bioequivalent and
pharmaceutically equivalent 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 products and the method of
manufacture. Process validation studies were conducted and the results were satisfactory. The
validation data showed comparability between batches and demonstrated consistent
manufacture.
23
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. The data demonstrate that the batches are compliant with the
proposed specifications. Certificates of Analysis have been provided for any reference
standards used.
Container Closure System

The finished product is licensed for marketing in polyamide (PA) / polyvinylchloride (PVC) /
aluminium foil blister strips, which are packaged with the Patient Information Leaflet (PIL)
into cardboard outer cartons in pack sizes of 14, 20, 28, 30, 50, 98 and 100 film-coated
tablets. 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 2 years has been set, which is satisfactory. Storage instructions are Do not store above
30C. Store in original package in order to protect from light and moisture.
Bioequivalence Study
A bioequivalence study was presented comparing the test product, Montelukast 10mg film-
coated tablets, to the reference product, Singulair 10mg film-coated tablets (Merck Sharp &
Dohme Limited).
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 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.
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 film-
coated tablets from a pharmaceutical point of view.
24
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 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 film-coated tablets from a non-
clinical point of view.
III.3 CLINICAL ASPECTS

INDICATIONS
Montelukast 10mg film-coated tablets are indicated in patients from 15 years of age.
Montelukast 10mg film-coated tablets are indicated in the treatment of asthma as add-on
therapy in those patients with mild to moderate, persistent asthma who are inadequately
controlled on inhaled corticosteroids and in whom as-needed short acting -2-agonists
provide inadequate clinical control of asthma.
In those asthmatic patients in whom montelukast is indicated in asthma, this medicine can
also provide symptomatic relief of seasonal allergic rhinitis.
Montelukast 10mg film-coated tablets are 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 SmPC.
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.
25
Pharmacokinetics bioequivalence study

The applications are supported by the bioequivalence study presented by the applicant
comparing the pharmacokinetic profiles of Montelukast 10mg film-coated tablets (test) and
Singulair 10mg film-coated tablets - Merck Sharp & Dohme Limited (reference). The study
was of an appropriate design and was conducted to principles of Good Clinical Practice
(GCP). Certificates of Analysis have been provided for the test and reference products.
This was a comparative, randomised, open-label, single-dose, 2-way crossover, 2-sequence

bioequivalence study conducted in 34 healthy, non-smoking, 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 LC-MS/MS analytical method.
The primary pharmacokinetic parameters for this study were Cmax, AUC0-t, and AUC0-.
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, AUC0-t, and AUC0-.
Results:
34 subjects were enrolled in the study; all 34 completed the study and were included in the
pharmacokinetic evaluation and statistical analysis.
Safety Overall, 5 subjects (14.7% of the study population receiving the test product)
experienced at least 1 adverse event that was possibly, probably, or definitely related to the
test product, and 1 subject (2.9% of the study population receiving the reference product)
experienced at least 1 adverse event that was possibly, probably, or definitely related to the
reference product. 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, 2-way, 2-sequence, single-dose crossover study
between the 10mg strength test and reference products. n=34 healthy subjects, dosed fasted; t=24 hours. Wash-
out period: 7 days
Geometric Least Squares Mean

Parameters 90% CI
Reference Test Product Ratio (Y/X) (Parametric)
Product (X) (Y) %
Cmax (ng/ml) 423.04 394.95 93% 84-104%
AUC0-t (ng.h/ml) 2730.89 2608.14 96% 88-103%
AUC0-(ng.h/ml) 2823.37 2691.84 95% 89-103%
AUC0- area under the plasma concentration-time curve from time zero to infinity
AUC0-t area under the plasma concentration-time curve from time zero to t hours
Cmax maximum plasma concentration
26
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, AUC0-t, and
AUC0- for montelukast fall within the acceptance criteria ranges of 80.00-125.00%, in line
with current guidelines.
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 those 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 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.
27
IV OVERALL CONCLUSION AND BENEFIT-RISK ASSESSMENT
QUALITY
The important quality characteristics of Montelukast 10mg film-coated 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 applicants Montelukast 10mg film-
coated, and the UK reference product, Singulair 10mg film-coated tablets (PL 00025/0358,
Merck Sharp & Dohme Limited).
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 final PIL text is in line with the SmPCs and is also in line with the CHMP article 30
harmonisation referral (CHMP/212107/08). User testing of the leaflet text has been accepted
based on a bridging report provided by the applicant making reference to the successful user-
testing of the PIL for Montelukast 4mg chewable tablets [UK/H/2576-84/01/DC].
The approved labelling text is satisfactory.
The MAH has submitted text versions only for the PIL and labelling, and has committed to
submitting mock-up livery to the relevant regulatory authorities for approval before packs are
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
applicants product, Montelukast 10mg film-coated 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.
28
Module 6
STEPS TAKEN AFTER INITIAL PROCEDURE - SUMMARY
Date Application Scope Outcome

submitted type
29

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PAR Montelukast 10mg film-coated tablets UK/H/2576-84/03/DC

Public Assessment Report

Montelukast 10mg film-coated tablets

Montelukast is a leukotriene receptor antagonist that blocks substances called leukotrienes.

Asthma is a long-term disease and includes:

Difficulty breathing caused by narrowed airways. This narrowing of airways

Symptoms of asthma include coughing, wheezing and chest tightness.

Module 1: Information about initial procedure Page 4

Module 2: Summaries of Product Characteristics Page 5

Module 3: Product Information Leaflet Page 12

Module 4: Labelling Page 17

Module 5: Scientific discussion during initial procedure Page 19

Module 6: Steps taken after initial procedure Page 29

Product Name Montelukast 10mg film-coated tablets

Type of Application Generic, Article 10.1

Active Substance Montelukast sodium

Form Film-coated tablets

Reference Member State UK

Concerned Member UK/H/2576/03/DC: Denmark, Finland, Norway, Sweden

Procedure Number UK/H/2576-84/03/DC

Timetable End of Procedure: Day 210 1st July 2010

1 NAME OF THE MEDICINAL PRODUCT

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Excipient: Lactose monohydrate 89.6 mg per tablet

For a full list of excipients, see section 6.1.

Montelukast is indicated in adults from 15 years of age.

4.2 Posology and method of administration

Therapy with Montelukast in relation to other treatments for asthma:

4.4 Special warnings and precautions for use

Montelukast should not be substituted for inhaled or oral corticosteroids.

This medicinal product contains lactose.

4.6 Pregnancy and lactation

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

Use during lactation

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

4.7 Effects on ability to drive and use machines

4.8 Undesirable effects

Body System Class Adult patients Paediatric patients

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

Psychiatric disorders: dream abnormalities including nightmares, hallucinations, insomnia,

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

Cardiac disorders: palpitations.

Respiratory, thoracic and mediastinal disorders: epistaxis.

Gastro-intestinal disorders: diarrhoea, dry mouth, dyspepsia, nausea, vomiting.

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

ATC-code: R03D C03

Significant reduction of exercise-induced bronchoconstriction (EIB) was demonstrated in a 12-week

In aspirin-sensitive asthmatic patients receiving concomitant inhaled and/or oral corticosteroids,

5.2 Pharmacokinetic properties

Biotransformation. Montelukast is extensively metabolised. In studies with therapeutic doses, plasma

5.3 Preclinical safety data

6.3 Shelf life

6.4 Special precautions for storage

6.5 Nature and contents of container

6.6 Special precautions for disposal

7 MARKETING AUTHORISATION HOLDER

8 MARKETING AUTHORISATION NUMBER(S)

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

10 DATE OF REVISION OF THE TEXT