Montelukast Mylan 5 mg Chewable Tablets

4.2 Posology and method of administration

Posology

The dosage for paediatric patients 6-14 years of age is one 5 mg chewable tablet daily to be taken in the evening.

No dosage adjustment within this age group is necessary.

General recommendations. The therapeutic effect of montelukast on parameters of asthma control occurs within one day. Patients should be advised to continue taking Montelukast Mylan 5 mg even if their asthma is under control, as well as during periods of worsening asthma.

No dosage adjustment is necessary for patients with renal insufficiency, or mild to moderate hepatic impairment. There are no data on patients with severe hepatic impairment. The dosage is the same for both male and female patients.

Montelukast Mylan 5 mg as an alternative treatment option to low-dose inhaled corticosteroids for mild, persistent asthma:
Montelukast is not recommended as monotherapy in patients with moderate persistent asthma. The use of montelukast as an alternative treatment option to low-dose inhaled corticosteroids for children with mild persistent asthma should only be considered for patients who do not have a recent history of serious asthma attacks that required oral corticosteroid use and who have demonstrated that they are not capable of using inhaled corticosteroids (see section 4.1). Mild persistent asthma is defined as asthma symptoms more than once a week but less thatn once a day, nocturnal symptoms more than twice a month but less than once a week, normal lung function between episodes. If satisfactory control of asthma is not achieved at follow-up (usually within one month), the need for an additional or different anti-inflammatory therapy based on the step system for asthma therapy should be evaluated. Patients should be periodically evaluated for their asthma control.

Therapy with Montelukast Mylan 5 mg in relation to other treatments for asthma.
When treatment with montelukast is used as add-on therapy to inhaled corticosteroids, Montelukast Mylan 5 mg should not be abruptly substituted for inhaled corticosteroids (see section 4.4).

10 mg tablets are available for adults and adolescents 15 years of age and older.

Paediatric population
Do not give Montelukast Mylan 5mg to children less than 6 years of age. The safety and efficacy of montelukast 5 mg chewable tablets in children less than 6 years of age has not been established.

4 mg chewable tablets are available for paediatric patients 2 to 5 years of age.
4 mg granules may be available for paediatric patients 6 months to 5 years of age.

Method of administration
For oral use.

The tablets are to be chewed before swallowing. If taken in connection with food, Montelukast Mylan 5 mg should be taken 1 hour before or 2 hours after food

4.4 Special warnings and precautions for use

Patients should be advised never to use oral montelukast to treat acute asthma attacks and to keep their usual appropriate rescue medication for this purpose readily available. If an acute attack occurs, a short-acting inhaled beta-agonist should be used. Patients should seek their doctors' advice as soon as possible if they need more inhalations of short-acting beta-agonists than usual.

Montelukast should not be abruptly substituted for inhaled or oral corticosteroids.

There are no data demonstrating that oral corticosteroids can be reduced when montelukast is given concomitantly.

In rare cases, patients on therapy with anti-asthma agents including montelukast may present with systemic eosinophilia, sometimes presenting with clinical features of vasculitis consistent with Churg-Strauss syndrome, a condition which is often treated with systemic corticosteroid therapy. These cases usually, but not always, have been sometimes associated with the reduction or withdrawal of oral corticosteroid therapy. Although a causal relationship with The possibility that leukotriene receptor antagonistsm has not been established, may be associated with the emergence of Churg-Strauss syndrome can neither be excluded nor established. Pphysicians 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 acetylsalicylic acid aspirin-sensitive asthma to avoid taking acetylsalicylic acid aspirin and other non-steroidal anti-inflammatory drugs.

Montelukast Mylan 5 mg contains aspartame, a source of phenylalanine. Patients with phenylketonuria should take into account that each chewable tablet contains phenylalanine in an amount equivalent to 1.12 mg phenylalanine per dose.

4.7 Effects on ability to drive and use machines

Montelukast has no or negligible influence on the ability to drive and use machines.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

Tabulated list of Adverse Reactions Post-marketing Experience

System Organ Class	Adverse Experience Term	Frequency Category*
Infections and infestations	upper respiratory infection†	Very Common
Blood and lymphatic system disorders	increased bleeding tendency	Rare
Immune system disorders	hypersensitivity reactions including anaphylaxis	Uncommon
	hepatic eosinophilic infiltration	Very Rare
Psychiatric disorders	dream abnormalities including nightmares, insomnia, somnambulism, anxiety, agitation including aggressive behaviour or hostility, depression, psychomotor hyperactivity (including irritability, restlessness, tremor§)	Uncommon
	disturbance in attention, memory impairment	Rare
	hallucinations, disorientation, suicidal thinking and behaviour (suicidality)	Very Rare
Nervous system disorders	dizziness, drowsiness, paraesthesia/hypoesthesia, seizure	Uncommon
Cardiac disorders	palpitations	Rare
Respiratory, thoracic and mediastinal disorders	epistaxis	Uncommon
	Churg-Strauss Syndrome (CSS) (see section 4.4), pulmonary eosinophilia	Very Rare
Gastrointestinal disorders	diarrhoea‡, nausea‡, vomiting‡	Common
	dry mouth, dyspepsia	Uncommon
Hepatobiliary disorders	elevated levels of serum transaminases (ALT, AST)	Common
	hepatitis (including cholestatic, hepatocellular, and mixed-pattern liver injury).	Very Rare
Skin and subcutaneous tissue disorders	rash‡	Common
	bruising, urticaria, pruritus	Uncommon
	angiooedema	Rare
	erythema nodosum, erythema multiforme	Very Rare
Musculoskeletal, connective tissue disorders	arthralgia, myalgia including muscle cramps	Uncommon
General disorders and administration site conditions	pyrexia‡	Common
	asthenia/fatigue, malaise, oedema,	Uncommon
*Frequency Category: Defined for each Adverse Experience Term Reaction by the incidence reported in the clinical trials data base: Very Common (≥1/10), Common (≥1/100 to <1/10), Uncommon (≥1/1,000 to <1/100), Rare (≥1/10,000 to <1/1,000), Very Rare (<1/10,000).   †This adverse experience, reported as Very Common in the patients who received montelukast, was also reported as Very Common in the patients who received placebo in clinical trials.   ‡This adverse experience, reported as Common in the patients who received montelukast, was also reported as Common in the patients who received placebo in clinical trials.   § Frequency Category: Rare

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.

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

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

5. PHARMACOLOGICAL PROPERTIES

5.1  Pharmacodynamic properties

Pharmacotherapeutic group: Leukotriene receptor antagonist,
ATC code: R03DC03

Mechanism of action
The cysteinyl leukotrienes (LTC4, LTD4, and 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) found in the human airway and cause airway actions, including bronchoconstriction, mucous secretion, vascular permeability, and eosinophil recruitment.

Pharmacodynamic effects
Montelukast is an orally active compound which binds with high affinity and selectivity to the CysLT1 receptor. In clinical studies, montelukast inhibits bronchoconstriction due to inhaled LTD4 at doses as low as 5 mg. Bronchodilation was observed within 2 hours of oral administration. The bronchodilation effect caused by a beta-agonist was additive to that caused by montelukast. Treatment with montelukast inhibited both early- and late- phase bronchoconstriction due to antigen challenge. Montelukast, compared with placebo, decreased peripheral blood eosinophils in adult and paediatric patients. In a separate study, treatment with montelukast significantly decreased eosinophils in the airways (as measured in sputum) and in peripheral blood eosinophils while improving clinical asthma control.

Clinical efficacy and safety
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 beta-agonist use ( 26.1% vs -4.6% change from baseline). Improvement in patient-reported daytime and nighttime asthma symptoms scores was significantly better than placebo.

 

Section 2:

Excipient(s) with known effect: Each chewable tablet contains 2.0 mg Aspartame (E 951).

Section 4.2:

PosologyMethod of administration:
For oral use.

The dosage for paediatric patients 6-14 years of age is one 5 mg chewable tablet daily to be taken in
the evening.

If taken in connection with food, Montelukast Mylan 5 mg should be taken 1 hour before or 2 hours
after food. No dosage adjustment within this age group is necessary.

General recommendations. The therapeutic effect of Mmontelukast Mylan 5 mg on parameters of
asthma control occurs within one day. Patients should be advised to continue taking Montelukast
Mylan 5 mg even if their asthma is under control, as well as during periods of worsening asthma.

Montelukast Mylan 5 mg is not recommended as monotherapy in patients with moderate persistent
asthma.

Therapy with Montelukast Mylan 5 mg in relation to other treatments for asthma.
When treatment with Mmontelukast Mylan 5 mg is used as add-on therapy to inhaled corticosteroids,
Montelukast Mylan 5 mg should not be abruptly substituted for inhaled corticosteroids (see section
4.4).
10 mg tablets are available for adults and adolescents 15 years of age and older.
5 mg chewable tablets are available for paediatric patients 6 to 14 years of age.
4 mg chewable tablets are available for paediatric patients 2 to 5 years of age.

Method of administration
For oral use.

The tablets are to be chewed before swallowing. If taken in connection with food, Montelukast Mylan
5 mg should be taken 1 hour before or 2 hours after food

Section 4.4:

Montelukast Mylan 5 mg should not be abruptly substituted for inhaled or oral corticosteroids.

There are no data demonstrating that oral corticosteroids can be reduced when montelukast is given
concomitantly.

In rare cases, patients on therapy with anti-asthma agents including montelukast may present with
systemic eosinophilia, sometimes presenting with clinical features of vasculitis consistent with Churg-
Strauss syndrome, a condition which is often treated with systemic corticosteroid therapy. These cases
usually, but not always, have been sometimes associated with the reduction or withdrawal of oral
corticosteroid therapy. Although a causal relationship with leukotriene receptor antagonism has not
beenThe possibility that leukotriene receptor antagonists may be associated with the emergence of
Churg-Strauss syndrome can neither be excluded nor established., pPhysicians 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 aspirinacetylsalicylic acidsensitive
asthma to avoid taking aspirin acetylsalicylic acid and other non-steroidal anti-inflammatory
drugs.

Section 4.5:
Montelukast Mylan 5 mg may be administered with other therapies routinely used in the prophylaxis
and chronic treatment of asthma.

Section 4.6:

Limited data from available pregnancy databases do not suggest a causal relationship between
Mmontelukast Mylan 5mg and malformations (i.e. limb defects) that have been rarely reported in
worldwide post marketing experience.

Section 4.7:
Montelukast Mylan 5 mg 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.

Section 4.8:
Montelukast has been evaluated in clinical studies in patients with persistent asthma as follows:

• 10 mg film-coated tablets in approximately 4000 adult and adolescent patients 15 years of age and
older, and
• 5 mg chewable tablets in approximately 1750 paediatric patients 6 to 14 years of age, and
• 4 mg chewable tablets in 851 paediatric patients 2 to 5 years of age.

Note: Changes to adverse table

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

Reporting of suspected adverse reactions:
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare
professionals are asked to report any suspected adverse reactions via
IMB HPRA Pharmacovigilance,
Earlsfort Terrace,
IRL- Dublin 2;
Tel: +353 1 6764971;
Fax: +353 1 6762517.
Website: www.imbhpra.ie;
eE-mail: imbpharmacovigilance@imb.iemedsafety@hpra.ie.

Section 4.9:

It is not known whether montelukast is dialyzsable by peritoneal- or hemo-dialysis.

Section 5.1:

The cysteinyl leukotrienes (LTC4, LTD4, and LTE4) are potent inflammatory eicosanoids released
from various cells including mast cells and eosinophils.

In a separate study, treatment with montelukast significantly decreased eosinophils in the
airways (as measured in sputum). In adult and paediatric patients 2 to 14 years of age, montelukast,
compared with placebo, decreased and in peripheral blood eosinophils while improving clinical
asthma control.

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 with placebo irrespective of concomitant
controller therapy (inhaled/nebulized corticosteroids or inhaled/nebulized sodium cromoglycate).
Sixty percent of patients were not on any other controller therapy. Montelukast improved daytime
symptoms (including coughing, wheezing, trouble breathing and activity limitation) and nighttime
symptoms compared with placebo. Montelukast also decreased "as-needed" beta-agonist use and
corticosteroid rescue for worsening asthma compared with placebo. Patients receiving montelukast
had more days without asthma than those receiving placebo. A treatment effect was achieved after the
first dose.

In a 12-month, placebo-controlled study in paediatric patients 2 to 5 years of age with mild asthma and
episodic exacerbations, montelukast 4 mg once daily significantly (p 0.001) reduced the yearly rate
of asthma exacerbation episodes (EE) compared with placebo (1.60 EE vs. 2.34 EE, respectively), [EE
defined as 3 consecutive days with daytime symptoms requiring beta-agonist use, or corticosteroids
(oral or inhaled), or hospitalization for asthma]. The percentage reduction in yearly EE rate was
31.9%, with a 95% CI of 16.9, 44.1.

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

Section 5.2:

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.

Section 6.1:

Formatting changes

Section 6.4:

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

Section 6.5:

PA/Aluminium/PE-Aluminium blisters in pack sizes of 7, 10, 14, 20, 28, 30, 50, 56, 98, 100, 112 or
200 tablets.

PA/Aluminium/PE-Aluminium perforated unit dose blisters within a cardboard carton containing pack
sizes of 28 x 1 chewable tablets.

Section 2:
Excipient(s) with known effect: Each chewable tablet contains 2.0 mg Aspartame (E 951).

For a the full list of excipients, see section 6.1.

Section 3:

A white to off-white coloured, round, biconvex tablet, 7.2mm in diameter debossed with “M” on one side and “MS2” on other side.

Section 4.3:
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Section 4.4:

These cases usually, but not always, have been sometimes associated with the reduction or withdrawal of oral corticosteroid therapy. The possibility that Although a causal relationship with leukotriene receptor antagonistsm may be associated with emergence of Churg-Strauss syndrome can neither be excluded nor has not been established., Pphysicians should be alert to eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy presenting in their patients.

Section 4.5:
The area under the plasma concentration curve (AUC) for montelukast was decreased approximately 40% in subjects with co-administration of phenobarbital. Since montelukast is metabolised by CYP 3A4, 2C8, and 2C9,caution should be exercised, particularly in children, when montelukast is coadministered with inducers of CYP 3A4, 2C8, and 2C9, such as phenytoin, phenobarbital and rifampicin.

In vitro studies have shown that montelukast is a substrate of CYP 2C8, and to a less significant
extent, of 2C9, and 3A4. In a clinical drug-drug interaction study involving montelukast and
gemfibrozil (an inhibitor of both CYP 2C8 and 2C9) gemfibrozil increased the systemic exposure of
montelukast by 4.4-fold. No routine dosage adjustment of montelukast is required upon coadministration with gemfibrozil or other potent inhibitors of CYP 2C8, but the physician should be
aware of the potential for an increase in adverse reactions.

Based on in vitro data, clinically important drug interactions with less potent inhibitors of CYP 2C8
(e.g., trimethoprim) are not anticipated. Co-administration of montelukast with itraconazole, a strong
inhibitor of CYP 3A4, resulted in no significant increase in the systemic exposure of montelukast.

Section 4.6:
Use during pregnancyPregnancy
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 Mylan 5mg and malformations (i.e. limb defects) that have been rarely reported in worldwide post marketing experience.

Montelukast Mylan 5 mg may be used during pregnancy only if it is considered to be clearly essential.

Use during lactationBreast-feeding
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.

Section 4.8:

Adverse reaction table updated.

Reporting of suspected adverse reactions:
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare
professionals are asked to report any suspected adverse reactions via

IMB Pharmacovigilance,
Earlsfort Terrace,
IRL- Dublin 2;
Tel: +353 1 6764971;
Fax: +353 1 6762517.
Website: www.imb.ie;
e-mail: imbpharmacovigilance@imb.ie

Section 5.2:
Cytochrome P450 2C8 is the major enzyme in the metabolism of montelukast. Additionally CYP 3A4
and 2C9 may have a minor contribution, although itraconazole, an inhibitor of CYP 3A4, was shown
not to change pharmacokinetic variables of montelukast in healthy subjects that received 10 mg
montelukast daily.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.

Section 6.3:
Blisters: 2 3 years

HDPE bottles: 3 years. Once open use within 100 days.

Section 6.4:

Do not store above 25oC. Store in the original package, in order to protect from light and moisture.

Section 6.6:

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

Section 9:
Date of last renewal: 21st June 2013

None provided