Sng ped 2005

SINGULAIR™ - Local Prescribing Information
SINGULAIR PAEDIATRIC 4 mg GRANULES
Pharmacotherapeutic group: Anti-Asthmatics for systemic use, Leukotriene receptor antagonist
ATC-code: R03D C03
1. NAME OF THE MEDICINAL PRODUCT
The cysteinyl leukotrienes (LTC4, LTD4, LTE4) are potent inflammatory eicosanoids released from various cells including mast cells and eosinophils. These
SINGULAIR® Paediatric 4 mg Granules
important pro-asthmatic mediators bind to cysteinyl leukotriene receptors (CysLT) found in the human airway and cause airway actions, including bronchocon-
striction, mucous secretion, vascular permeability, and eosinophil recruitment.
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Montelukast is an orally active compound which binds with high affinity and selectivity to the CysLT1 receptor. In clinical studies, montelukast inhibits bron-
One sachet of granules contains montelukast sodium, which is equivalent to 4 mg montelukast.
choconstriction due to inhaled LTD4 at doses as low as 5 mg. Bronchodilation was observed within 2 hours of oral administration. The bronchodilation effect
For excipients, see 6.1.
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
3. PHARMACEUTICAL FORM
with montelukast significantly decreased eosinophils in the airways (as measured in sputum). In adult and paediatric patients 2 to 14 years of age, montelukast,
Granules.
compared with placebo, decreased peripheral blood eosinophils while improving clinical asthma control.
White granules.
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. CLINICAL PARTICULARS
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 beclometha-
4.1 Therapeutic indications
sone plus montelukast vs beclomethasone, respectively for FEV1: 5.43% vs 1.04%; ?-agonist use: -8.70% vs 2.64%). Compared with inhaled beclomethasone
‘Singulair’ is indicated in the treatment of asthma as add-on therapy in those patients with mild to moderate persistent asthma who are inadequately controlled
(200 ?g twice daily with a spacer device), montelukast demonstrated a more rapid initial response, although over the 12-week study, beclomethasone provided
on inhaled corticosteroids and in whom ‘as-needed’ short acting ?-agonists provide inadequate clinical control of asthma.
a greater average treatment effect (% change from baseline for montelukast vs beclomethasone, respectively for FEV1: 7.49% vs 13.3%; ?-agonist use: -28.28%
‘Singulair’ is also indicated in the prophylaxis of asthma in which the predominant component is exercise-induced bronchoconstriction.
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 treat-
4.2 Posology and method of administration
ed with montelukast achieved the same response).
The dosage for paediatric patients 6 months to 5 years of age is one sachet of 4-mg granules daily to be taken in the evening. No dosage adjustment within this
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
age group is necessary. The experience in use in paediatric patients 6 to 12 months of age is limited. Safety and efficacy below 6 months of age have not been
(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
established.
+8.2% change from baseline).
Administration of ‘Singulair’ granules
In a 12-week, placebo-controlled study in paediatric patients 2 to 5 years of age, montelukast 4 mg once daily improved parameters of asthma control compared
‘Singulair’ granules can be administered either directly in the mouth, or mixed with a spoonful of cold or room temperature soft food (e.g. applesauce, ice
with placebo irrespective of concomitant controller therapy (inhaled/nebulised corticosteroids or inhaled/nebulised sodium cromoglycate). Sixty percent of
cream, carrots and rice). The sachet should not be opened until ready to use. After opening the sachet, the full dose of ‘Singulair’ granules must be administered
patients were not on any other controller therapy. Montelukast improved daytime symptoms (including coughing, wheezing, trouble breathing and activity limi-
immediately (within 15 minutes). If mixed with food, ‘Singulair’ granules must not be stored for future use. ‘Singulair’ granules are not intended to be dissolved
tation) and nighttime symptoms compared with placebo. Montelukast also decreased ‘as-needed’ ?-agonist use and corticosteroid rescue for worsening asthma
in liquid for administration. However, liquids may be taken subsequent to administration. ‘Singulair’ granules can be administered without regard to the timing
compared with placebo. Patients receiving montelukast had more days without asthma than those receiving placebo. A treatment effect was achieved after the
of food ingestion.
first dose.
General recommendations:The therapeutic effect of ‘Singulair’ on parameters of asthma control occurs within one day. Patients should be advised to continue
Efficacy of montelukast is supported in paediatric patients 6 months to 2 years of age by extrapolation from the demonstrated efficacy in patients 2 years of age
taking ‘Singulair’ even if their asthma is under control, as well as during periods of worsening asthma.
and older with asthma, and is based on similar pharmacokinetic data, as well as the assumption that the disease course, pathophysiology and the drug’s effect
No dosage adjustment is necessary for patients with renal insufficiency, or mild to moderate hepatic impairment. There are no data on patients with severe
are substantially similar among these populations.
hepatic impairment. The dosage is the same for both male and female patients.
Significant reduction of exercise-induced bronchoconstriction (EIB) was demonstrated in a 12-week study in adults (maximal fall in FEV1 22.33% for mon-
Therapy with ‘Singulair’ in relation to other treatments for asthma.
telukast 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
‘Singulair’ can be added to a patient’s existing treatment regimen.
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%;
B-agonist therapy: ‘Singulair’ can be added to the treatment regimen of patients who are not adequately controlled on ‘as-needed’ short acting ?-agonist. When
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.
a clinical response is evident (usually after the first dose), the patient may be able to decrease the use of ‘as-needed’ short acting B-agonist.
In aspirin-sensitive asthmatic patients receiving concomitant inhaled and/or oral corticosteroids, treatment with montelukast, compared with placebo, resulted
Inhaled corticosteroids: Treatment with ‘Singulair’ can be used as add-on therapy in patients when other agents, such as inhaled corticosteroids, provide inade-
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
quate clinical control. ‘Singulair’ should not be substituted for inhaled corticosteroids. (See section 4.4 ‘Special warnings and precautions for use’.)
baseline).
10-mg tablets are available for adults 15 years of age and older.
5-mg chewable tablets are available for paediatric patients 6 to 14 years of age.
5.2 Pharmacokinetic properties
4-mg chewable tablets are available as an alternative formulation for paediatric patients 2 to 5 years of age.
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 influ-
4.3 Contraindications
enced by a standard meal. Safety and efficacy were demonstrated in clinical trials where the 10mg film-coated tablet was administered without regard to the
Hypersensitivity to the active substance or to any of the excipients.
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
4.4 Special warnings and special precautions for use
decreased to 63% by a standard meal.
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
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
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
mean Cmax is 66% higher while mean Cmin is lower than in adults receiving a 10-mg tablet.
they need more inhalations of short-acting ?-agonists than usual.
The 4-mg granule formulation is bioequivalent to the 4-mg chewable tablet when administered to adults in the fasted state. In paediatric patients 6 months to 2
Montelukast should not be substituted for inhaled or oral corticosteroids.
years of age, Cmax is achieved 2 hours after administration of the 4-mg granules formulation. Cmax is nearly 2-fold greater than in adults receiving a 10-mg
There are no data demonstrating that oral corticosteroids can be reduced when montelukast is given concomitantly.
tablet. The co-administration of applesauce or a high-fat standard meal with the granule formulation did not have a clinically meaningful effect on the pharma-
In rare cases, patients on therapy with anti-asthma agents including montelukast may present with systemic eosinophilia, sometimes presenting with clinical
cokinetics of montelukast as determined by AUC (1225.7 vs 1223.1 ng.hr/mL with and without applesauce, respectively, and 1191.8 vs 1148.5 ng.hr/mL with and
features of vasculitis consistent with Churg-Strauss syndrome, a condition which is often treated with systemic corticosteroid therapy. These cases usually, but
without a high-fat standard meal, respectively).
not always, have been associated with the reduction or withdrawal of oral corticosteroid therapy. The possibility that leukotriene receptor antagonists may be
Distribution: Montelukast is more than 99% bound to plasma proteins. The steady-state volume of distribution of montelukast averages 8-11 litres. Studies in
associated with emergence of Churg-Strauss syndrome can neither be excluded nor established. Physicians should be alert to eosinophilia, vasculitic rash,
rats with radiolabeled montelukast indicate minimal distribution across the blood-brain barrier. In addition, concentrations of radiolabeled material at 24 hours
worsening pulmonary symptoms, cardiac complications, and/or neuropathy presenting in their patients. Patients who develop these symptoms should be
post-dose were minimal in all other tissues.
reassessed and their treatment regimens evaluated.
Biotransformation: Montelukast is extensively metabolised. In studies with therapeutic doses, plasma concentrations of metabolites of montelukast are unde-
Safety and efficacy have not yet been established in the paediatric population below 6 months of age.
tectable 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
4.5 Interaction with other medicinal products and other forms of Interaction
in vitro results in human liver microsomes, therapeutic plasma concentrations of montelukast do not inhibit cytochromes P450 3A4, 2C9, 1A2, 2A6, 2C19, or 2D6.
Montelukast may be administered with other therapies routinely used in the prophylaxis and chronic treatment of asthma. In drug-interactions studies, the rec-
The contribution of metabolites to the therapeutic effect of montelukast is minimal.
ommended clinical dose of montelukast did not have clinically important effects on the pharmacokinetics of the following drugs: theophylline, prednisone, pred-
Elimination: The plasma clearance of montelukast averages 45 ml/min in healthy adults. Following an oral dose of radiolabeled montelukast, 86% of the radioac-
nisolone, oral contraceptives (ethinyl estradiol/norethindrone 35/1), terfenadine, digoxin and warfarin.
tivity was recovered in 5-day faecal collections and <0.2% was recovered in urine. Coupled with estimates of montelukast oral bioavailability, this indicates that
The area under the plasma concentration curve (AUC) for montelukast was decreased approximately 40% in subjects with co-administration of phenobarbital.
montelukast and its metabolites are excreted almost exclusively via the bile.
Since montelukast is metabolised by CYP 3A4, caution should be exercised, particularly in children, when montelukast is coadministered with inducers of CYP
Characteristics in patients: No dosage adjustment is necessary for the elderly or mild to moderate hepatic insufficiency. Studies in patients with renal impair-
3A4, such as phenytoin, phenobarbital and rifampicin.
ment 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).
4.6 Pregnancy and lactation
With high doses of montelukast (20- and 60-fold the recommended adult dose), a decrease in plasma theophylline concentration was observed. This effect was
Since there are no controlled studies in pregnant or nursing women, montelukast should not be used during pregnancy or in nursing mothers unless it is consid-
not seen at the recommended dose of 10 mg once daily.
ered to be clearly essential. (See section 5.3 ‘Preclinical safety data’.)
5.3 Preclinical safety data
4.7 Effects on ability to drive and use machines
In animal toxicity studies, minor serum biochemical alterations in ALT, glucose, phosphorus and triglycerides were observed which were transient in nature. The
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.
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 sys-
4.8 Undesirable effects
temic exposure seen at the clinical dose). In animal studies, montelukast did not affect fertility or reproductive performance at systemic exposure exceeding the
Montelukast has been evaluated in clinical studies as follows:
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-
• 10-mg film-coated tablets in approximately 4,000 adult patients 15 years of age and older
fold the clinical systemic exposure). In studies in rabbits, a higher incidence of incomplete ossification, compared with concurrent control animals, was seen at
• 5-mg chewable tablets in approximately 1,100 paediatric patients 6 to 14 years of age.
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
• 4-mg chewable tablets in 573 paediatric patients 2 to 5 years of age, and
the placental barrier and is excreted in breast milk of animals.
• 4-mg granules in 175 paediatric patients 6 months to 2 years of age.
No deaths occurred following a single oral administration of montelukast sodium at doses up to 5,000 mg/kg in mice and rats (15,000 mg/m2 and 30,000 mg/m2
The following drug-related adverse reactions in placebo-controlled clinical studies were reported commonly (>1/100, <1/10) in patients treated with mon-
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
telukast and at a greater incidence than in patients treated with placebo:
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).
Body System Class Adult Patients
Paediatric Patients Paediatric Patients Paediatric Patients
Montelukast was neither mutagenic in in vitro and in vivo tests nor tumorigenic in rodent species.
15 years and older
6 to 14 years old
2 to 5 years old
6 months up to 2 years old
(two 12-week
(one 8-week
(one 12-week
(one 6-week
6. PHARMACEUTICAL PARTICULARS
studies; n=795)
study; n=201)
study; n=461)
study; n=175)
6.1 List of excipients
Body as a whole
abdominal pain
Mannitol, hydroxypropyl cellulose, and magnesium stearate.
6.2 Incompatibilities
Digestive system
diarrhoea
Not applicable.
disorders
UK PAGE 10
Nervous system
headache
headache
hyperkinesia
6.3 Shelf life
/psychiatric
Respiratory system
6.4 Special precautions for storage
disorders
Store in the original package.
Skin/skin
eczematous dermatitis, rash
6.5 Nature and contents of container
appendages
Packaged in polyethylene/aluminum/polyester sachet in:
disorder
Cartons of 7, 20, 28 and 30 sachets.
Not all pack sizes may be marketed.
With prolonged treatment in clinical trials with a limited number of patients for up to 2 years for adults, and up to 6 months for paediatric patients 6 to 14 years
of age, the safety profile did not change.
6.6 Instructions for use and handling
Cumulatively, 502 paediatric patients 2 to 5 years of age were treated with montelukast for at least 3 months, 338 for 6 months or longer, and 256 patients for
No special requirements.
12 months or longer. With prolonged treatment, the safety profile did not change in these patients either.
The safety profile in paediatric patients 6 months to 2 years of age did not change with treatment up to 3 months.
7. MARKETING AUTHORISATION HOLDER
The following adverse reactions have been reported in post-marketing use very rarely:
Merck Sharp & Dohme Limited
Body as whole: asthenia/fatigue, malaise, oedema, hypersensitivity reactions including anaphylaxis, angioedema, urticaria, pruritus, rash and one isolated report
Hertford Road
of hepatic eosinophilic infiltration.
Hoddesdon
Nervous system/psychiatric: dizziness, dream abnormalities including nightmares, hallucinations, drowsiness, insomnia, paraesthesia/hypoesthesia, irritability,
Hertfordshire EN11 9BU, UK
agitation including aggressive behaviour, restlessness, seizure.
Musculo-skeletal disorders: arthralgia, myalgia including muscle cramps.
8. MARKETING AUTHORISATION NUMBER(S)
Digestive system disorders: diarrhoea, dry mouth, dyspepsia, nausea, vomiting.
PL 0025/0440
Hepato-biliary disorders: elevated levels of serum transaminases (ALT, AST), cholestatic hepatitis.
Cardiovascular disorders: increased bleeding tendency, bruising, palpitations.
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
Very rare cases of Churg-Strauss Syndrome (CSS) have been reported during montelukast treatment in asthmatic patients. (see Section 4.4 ‘Special warnings
14 February 2003.
and precautions for use’).
UK Page 11
4.9 Overdose
10. DATE OF REVISION OF THE TEXT
No specific information is available on the treatment of overdosage with montelukast. In chronic asthma studies, montelukast has been administered at doses
December 2003.
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.
LEGAL CATEGORY
There have been reports of acute overdosage in children in post-marketing experience and clinical studies of up to at least 150 mg/day with montelukast. The
clinical and laboratory findings observed were consistent with the safety profile in adults and older paediatric patients. There were no adverse experiences
reported in the majority of overdosage reports. The most frequent adverse experiences observed were thirst, somnolence, mydriasis, hyperkinesia, and abdomi-
® denotes registered trademark of Merck & Co., Inc., Whitehouse Station, NJ, USA.
nal pain.
Merck Sharp & Dohme Limited 2004. All rights reserved.
It is not known whether montelukast is dialysable by peritoneal- or haemo-dialysis.
SPC.SGA-OG.03.UK/IRL.0953 (W25)
IRL PAGE 10
5. PHARMACOLOGICAL PROPERTIES
LPC-SNG/OG-ME-Dec-2003-20050229
5.1 Pharmacodynamic properties

Source: http://singulair.ae/secure/downloads/resources/pi/SNG_OG_LPC.pdf