Singulair 10 mg/5 mg/4 mg Film-Coated Tablets

SINGULAIR 10 mg Film-coated Tablets are indicated in adults and children 15 years of age and older for the prophylaxis and chronic treatment of atopic asthma. In those adult asthmatic patients, in whom SINGULAIR is indicated in asthma, SINGULAIR may also provide some symptomatic relief of seasonal allergic rhinitis. SINGULAIR 5 mg Chewable Tablets are indicated in paediatric patients over 6 years of age for the prophylaxis and chronic treatment of atopic asthma. SINGULAIR 4 mg Chewable Tablets and SINGULAIR SPRINKLES are indicated in paediatric patients 2 to 5 years of age for the prophylaxis and chronic treatment of atopic asthma.

SINGULAIR should be taken once daily in the evening. SINGULAIR can be taken with or without food.

SINGULAIR 10 mg Film-coated Tablets
Adults and Children 15 years of age and older with atopic asthma
One 10 mg film-coated tablet daily. Clinical studies in adults 15 years of age and older did not demonstrate additional clinical benefit to montelukast doses above 10 mg once daily.

SINGULAIR 5 mg Chewable Tablets
Paediatric patients 6 to 14 years of age with atopic asthma
One 5 mg chewable tablet daily.

SINGULAIR 4 mg Chewable Tablets
Paediatric patients 2 to 5 years of age with atopic asthma
One 4 mg chewable tablet daily.

SINGULAIR SPRINKLES
Paediatric patients 2 to 5 years of age with atopic asthma
One packet of SPRINKLES daily. SINGULAIR SPRINKLES can be administered either directly into the mouth, or mixed with a spoonful of cold or room temperature soft food (e.g. apple sauce). The packet should only be opened directly before use, and the full dose of SINGULAIR SPRINKLES must be administered immediately (within 15 minutes). Once mixed with food, SINGULAIR SPRINKLES must not be stored for future use. SINGULAIR SPRINKLES are not intended to be dissolved in liquid. However, liquids may be taken subsequent to administration.

A therapeutic effect of SINGULAIR on parameters of asthma control occurs within one day. Patients should be advised to continue taking SINGULAIR while their asthma is controlled, as well as during periods of worsening asthma. No dosage adjustment is necessary for the elderly, paediatric patients, for patients with renal insufficiency, or mild-to-moderate hepatic impairment. Therapy with SINGULAIR in relation to other treatments for asthma SINGULAIR can be added to a patientu2019s existing treatment regimen. Reduction in Concomitant Therapy Bronchodilator Treatments: SINGULAIR can be added to the treatment regimen of patients who are not adequately controlled on bronchodilator alone. When a clinical response is evident (usually after the first dose), the patientu2019s bronchodilator therapy may be reduced as tolerated. Inhaled Corticosteroids: A reduction in the corticosteroid dose can be made as tolerated. The dose should be reduced gradually with medical supervision. SINGULAIR should not be abruptly substituted for inhaled corticosteroids.

• Hypersensitivity to montelukast or to any component of SINGULAIR.
• SINGULAIR 10 mg Film-coated Tablets
  Children below the age of 15 years as safety and efficacy have not been demonstrated.
• SINGULAIR 5 mg Chewable Tablets
  Children below the age of 6 years, as safety and efficacy have not been demonstrated.
• SINGULAIR 4 mg Chewable Tablets and SPRINKLES
  Children below the age of 2 years, as safety and efficacy have not been demonstrated.

SINGULAIR is not indicated in the reversal of bronchospasm in acute asthma attacks, including status asthmaticus as the efficacy of SINGULAIR has not been established for the treatment of acute asthma attacks.

Eosinophilic conditions
Patients on therapy with SINGULAIR may present with eosinophilia, sometimes presenting with clinical features of vasculitis consistent with Churg-Strauss syndrome, a condition which is often treated with systemic corticosteroid therapy. These events usually, but not always, have been associated with the reduction of oral corticosteroid therapy. Medical practitioners should be on the alert for patients presenting with eosinophilia, vasculitic rash, worsening of pulmonary symptoms, cardiac complications, and/or neuropathy.

Neuropsychiatric events
Neuropsychiatric events have been reported in adult, adolescent and paediatric patients taking SINGULAIR. Post-marketing reports with SINGULAIR use include agitation, aggressive behaviour or hostility, anxiousness, depression, disorientation, disturbance in attention, abnormal dreams, hallucinations, insomnia, irritability, memory impairment, restlessness, somnambulism, suicidal ideation and behaviour (including suicide), tic and tremor. Patients and medical practitioners should be alert for neuropsychiatric events. Patients should be instructed to notify their medical practitioners if these changes occur. Medical practitioners should carefully evaluate the risks and benefits of continuing treatment with SINGULAIR if such events occur.

Hypersensitivity to aspirin
Patients with a known hypersensitivity to aspirin should continue avoiding aspirin and non-steroidal anti-inflammatory drugs (NSAIDs) while taking SINGULAIR. Although SINGULAIR is effective in improving airway function in asthmatics, it has not been demonstrated to reduce the bronchoconstrictor response to aspirin or other NSAIDs in aspirin-sensitive asthmatic patients.

Hepatic impairment
The metabolism of montelukast may be decreased in patients with mild to moderate hepatic impairment and clinical evidence of cirrhosis. The half-life may be slightly prolonged; however, dosage adjustment is not necessary. No data are available for patients with severe hepatic impairment.

General
SINGULAIR is not indicated for use in the reversal of bronchospasm in acute asthma attacks, including status asthmaticus. Patients should be advised to have appropriate rescue medication available. During acute exacerbations of asthma, therapy with SINGULAIR can be continued. Patients should be advised to take SINGULAIR daily as prescribed, even if they are asymptomatic, as well as during periods of worsening of asthma, and to contact their medical practitioners if their asthma is not well controlled. Medical attention should be sought if more than the prescribed maximum number of inhalations of short-acting bronchodilator treatment for a 24-hour period, are needed. SINGULAIR should not be used as monotherapy for the prophylactic treatment of exercise-induced bronchospasm. Patients should continue with their usual inhaled preventer therapy and have a short-acting inhaled beta agonist available for rescue, should they experience exacerbations of asthma after exercise. SINGULAIR should not be abruptly substituted for inhaled or oral corticosteroids. The dose of the corticosteroid therapy may be gradually tapered, under medical supervision. To ensure safe and appropriate use, patients should be advised to read the section on u201cWarnings and precautionsu201d in the Patient Information Leaflet.

SINGULAIR 10 mg Film-coated Tablets
Galactose intolerance
SINGULAIR 10 mg Film-coated Tablets contains lactose. Patients with the rare hereditary conditions of galactose intolerance e.g. galactosaemia, Lapp lactose deficiency or glucose-galactose malabsorption should not take SINGULAIR 10 mg Film-coated Tablets.

SINGULAIR 4 mg and 5 mg Chewable Tablets
Phenylalanine
Phenylketonurics: Phenylketonuric patients should be informed that the chewable tablets contain phenylalanine (a component of aspartame): 0,842 mg per 5 mg chewable tablet and 0,674 mg per 4mg chewable tablet. It may be harmful for patients with phenylketonuria.

SINGULAIR may be administered together with other therapies routinely used in the prophylaxis and chronic treatment of atopic asthma, and seasonal allergic rhinitis. In medicine interaction studies, the recommended clinical dose of montelukast did not have clinically important effects on the pharmacokinetics of the following medicines: Theophylline, prednisone, prednisolone, oral contraceptives (ethinyl oestradiol/norethindrone 35 mcg /1 mg), digoxin and warfarin. The area under the plasma concentration - time curve (AUC) for montelukast was decreased approximately 40 % in subjects with co-administration of phenobarbitone. No dosage adjustment for SINGULAIR is recommended. Clinical monitoring is recommended when potent hepatic enzyme inducers (such as ritonavir, phenytoin, phenobarbitone, rifampicin, or St Johnu2019s wort are given with SINGULAIR. In vitro studies have shown that montelukast is an inhibitor of isoenzyme CYP2C8. However, data from an interaction study involving montelukast and rosiglitazone (a substrate representative of medicines primarily metabolised by isoenzyme CYP2C8) demonstrated that montelukast did not significantly inhibit isoenzyme CYP2C8 in vivo. Therefore, SINGULAIR is not anticipated to alter the metabolism of medicines metabolised by isoenzyme (CYP2C8) (e.g. paclitaxel, rosiglitazone, and repaglinide.) In vitro studies have shown that montelukast is a substrate of CYP2C8, CYP2C9, and CYP3A4. Data from an interaction study involving montelukast and gemfibrozil (an inhibitor of both CYP2C8 and CYP2C9) demonstrated that gemfibrozil increased the systemic exposure of montelukast by 4,4-fold. Co-administration of itraconazole, a strong CYP3A4 inhibitor, with gemfibrozil and montelukast did not further increase the systemic exposure of montelukast. The effect of gemfibrozil on systemic exposure of montelukast is not considered to be clinically meaningful based on clinical safety data with doses greater than the 10 mg approved dose in adults (e.g., 200 mg/day to adult patients for 22 weeks, and up to 900 mg/day to patients for approximately one week) where clinically important adverse experiences were not observed. Therefore, no dosage adjustment of SINGULAIR is required upon co-administration with gemfibrozil. Based on in vitro data, important interactions with other known inhibitors of CYP2C8 (e.g., trimethoprim) are not anticipated. In addition, co-administration of montelukast with itraconazole alone resulted in no significant increase in the systemic exposure of montelukast.

Pregnancy
The safety of SINGULAIR in pregnant and lactating women has not been established. Available data from published prospective and retrospective cohort studies with montelukast use in pregnant women evaluating major birth defects have not established a drug-associated risk. Available studies have methodologic limitations, including small sample size, in some cases retrospective data collection, and inconsistent comparator groups.

Breastfeeding
It is not known if SINGULAIR is excreted in human milk. Women using SINGULAIR should not breastfeed their infants.

SINGULAIR may cause side effects such as dizziness or drowsiness, which may affect the ability to drive. Patients should therefore be advised not to drive or operate machinery until their individual susceptibility to SINGULAIR is known.

Side effects generally did not require discontinuation of therapy. The following medicine related adverse reactions in placebo-controlled clinical studies were reported in patients with asthma treated with SINGULAIR and at a greater incidence than in patients treated with placebo. The adverse reactions are listed by system organ class and frequency category. Frequency categories: Very common (u22651/10); Common (u22651/100 to u02c21/10); Uncommon (u22651/1 000 to u02c21/100); rare (u22651/10 000 to u02c21/1 000)

Adult and Adolescent Patients 15 years and older (two 12 week studies; n=795)
Paediatric Patients 6 to 14 years old (one 8 week study; n=201)
Paediatric Patients 2 to 5 years old (one 12 week study; n=461)

System Organ Class Adverse Reaction Frequency Adverse Reaction Frequency Adverse Reaction Frequency

Ear and labyrinth disorders
Vertigo Uncommon a

Eye disorders
Blepharospasm Uncommon a
Mydriasis Uncommon a

Gastrointestinal disorders
Abdominal discomfort Uncommon a
Abdominal pain Uncommon
Abdominal pain upper Uncommon
Bowel movement irregularity Uncommon a
Diarrhoea Uncommon
Diarrhoea Uncommon a
Dry mouth Uncommon
Dyspepsia Uncommon
Flatulence Uncommon
Flatulence Uncommon a
Nausea Uncommon
Salivary hypersecretion Uncommon a
Vomiting Uncommon

General disorders and administration site conditions
Chest pain Uncommon a
Fatigue Uncommon
Irritability Uncommon a
Thirst Common

Immune System disorders
Decreased immune responsiveness Uncommon a

Investigations
Alanine aminotransferase increased Uncommon
Aspartate aminotransferase increased Uncommon
Aspartate aminotransferase increased Uncommon

Eosinophil count increased Uncommon a
Haematocrit decreased Uncommon
Haemoglobin decreased Uncommon
White blood cell count decreased Uncommon
White blood cell count decreased Uncommon a

Metabolism and nutrition disorders
Increased appetite Uncommon a

Musculoskeletal and connective tissue disorders
Arthralgia Uncommon
Back pain Uncommon a
Back pain Uncommon a
Muscle spasms Uncommon a
Muscular weakness Uncommon a
Myalgia Uncommon a
Myalgia Uncommon a
Pain in extremity Uncommon a

Nervous system disorders
Dizziness Uncommon
Dizziness Uncommon a
Headache Common
Headache Common
Headache Uncommon a
Hypersomnia Uncommon
Paraesthesia Uncommon a
Somnolence Uncommon
Tremor Uncommon a
Tremor Uncommon a

Psychiatric disorders
Insomnia Uncommon
Insomnia Uncommon
Libido decreased Uncommon a
Mood swings Uncommon a

Renal and urinary disorders
Enuresis Uncommon a

Respiratory, thoracic and mediastinal disorders
Asthma Uncommon
Asthma Uncommon a
Cough Uncommon a
Dysphonia Uncommon a
Dysphonia Uncommon a
Dyspnoea Uncommon a
Epistaxis Uncommon a
Oropharyngeal pain Uncommon a
Postnasal drip Uncommon a
Respiratory tract congestion Uncommon a
Rhinitis allergic Uncommon a

Skin and subcutaneous tissue disorders
Acne Uncommon a
Night sweats Uncommon a
Pruritus generalised Uncommon a
Rash Uncommon
Rash pruritic Uncommon a

Vascular disorders
Hypertension Uncommon a
Hypertension Uncommon a

a Reported in 1 patient in the montelukast group. 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.

Patients on therapy with SINGULAIR may present with systemic eosinophilia, sometimes presenting with clinical features of vasculitis consistent with Churg-Strauss syndrome (see section 4.4).

Post-Marketing Experience
The following side effects have been reported in post-marketing use: Infections and infestations: upper respiratory tract infections Blood and lymphatic system disorders: increased bleeding tendency, thrombocytopenia Immune system disorders: hypersensitivity reactions including anaphylaxis, hepatic eosinophilic infiltration Psychiatric disorders: abnormal dreams, dysphemia (stuttering), hallucinations, agitation including aggressive behaviour or hostility, anxiousness, depression, disorientation, disturbance in attention, insomnia, memory impairment, obsessive-compulsive symptoms, psychomotor hyperactivity (including irritability, restlessness, and tremor) somnambulism, suicidal ideation and behaviour (suicidality), tic Nervous system disorders: dizziness, drowsiness, paraesthesia/hypoaesthesia, seizure Cardiac disorders: palpitations Respiratory, thoracic and mediastinal disorders: epistaxis, pulmonary eosinophilia, and Churg-Strauss syndrome Gastrointestinal disorders: diarrhoea, dyspepsia, nausea, vomiting Hepatobiliary disorders: increased alanine aminotransferase (ALT) and aspartate aminotransferase (AST), hepatitis (including cholestatic, hepatocellular and mixed-pattern liver injury) Skin and subcutaneous tissue disorders: angioedema, bruising, erythema multiforme, erythema nodosum, pruritus, rash, urticaria Musculoskeletal and connective tissue disorders: arthralgia, myalgia, including muscle cramps Renal and urinary disorders: enuresis in children General disorders and administration sites conditions: oedema, pyrexia, asthenia/fatigue

There were no adverse experiences reported in the majority of overdosage reports. The most frequently occurring adverse experiences included abdominal pain, somnolence, thirst, headache, vomiting and psychomotor hyperactivity. In chronic asthma studies, SINGULAIR 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. No specific information is available on the treatment of overdosage with SINGULAIR. Treatment is symptomatic and supportive. It is not known whether montelukast is dialysable by either peritoneal or haemodialysis.