Special Warning : אזהרת שימוש

5       WARNINGS AND PRECAUTIONS
5.1 Neuropsychiatric Events
Serious neuropsychiatric (NP) events have been reported with use of SINGULAIR. These postmarketing reports have been highly variable and included, but were not limited to, agitation, aggressive behavior or hostility, anxiousness, depression, disorientation, disturbance in attention, dream abnormalities, dysphemia (stuttering), hallucinations, insomnia, irritability, memory impairment, obsessive-compulsive symptoms, restlessness, somnambulism, suicidal thoughts and behavior (including suicide), tic, and tremor. NP events have been reported in adult, adolescent, and pediatric patients with and without a previous history of psychiatric disorder. NP events have been reported mostly during SINGULAIR treatment, but some were reported after SINGULAIR discontinuation. Animal studies showed that montelukast distributes into the brain in rats [see Clinical Pharmacology (12.3)]; however, the mechanisms underlying SINGULAIR- associated NP events are currently not well understood. Based upon the available data, it is difficult to identify risk factors for or quantify the risk of NP events with SINGULAIR use.

Because of the risk of NP events, the benefits of SINGULAIR may not outweigh the risks in some patients, particularly when the symptoms of disease may be mild and adequately treated with alternative therapies.
Reserve use of SINGULAIR for patients with allergic rhinitis who have an inadequate response or intolerance to alternative therapies [see Indications and Usage (1.3)]. In patients with asthma or exercise- induced bronchoconstriction, consider the benefits and risks before prescribing SINGULAIR.

Discuss the benefits and risks of SINGULAIR use with patients and caregivers when prescribing SINGULAIR. Advise patients and/or caregivers to be alert for changes in behavior or for new NP symptoms when taking SINGULAIR. If changes in behavior are observed, or if new NP symptoms or suicidal thoughts and/or behavior occur, advise patients to discontinue SINGULAIR and contact a healthcare provider immediately. In many cases, symptoms resolved after stopping SINGULAIR therapy; however, in some cases symptoms persisted after discontinuation of SINGULAIR. Therefore, continue to monitor and provide supportive care until symptoms resolve. Re-evaluate the benefits and risks of restarting treatment with SINGULAIR if such events occur.

5.2 Acute Asthma
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. Therapy with SINGULAIR can be continued during acute exacerbations of asthma. Patients who have exacerbations of asthma after exercise should have available for rescue a short-acting inhaled β-agonist.

5.3 Concomitant Corticosteroid Use
While the dose of inhaled corticosteroid may be reduced gradually under medical supervision, SINGULAIR should not be abruptly substituted for inhaled or oral corticosteroids.

5.4 Aspirin Sensitivity
Patients with known aspirin sensitivity should continue avoidance of aspirin or non-steroidal anti- inflammatory agents while taking SINGULAIR. Although SINGULAIR is effective in improving airway function in asthmatics with documented aspirin sensitivity, it has not been shown to truncate bronchoconstrictor response to aspirin and other non-steroidal anti-inflammatory drugs in aspirin-sensitive asthmatic patients [see Clinical Studies (14.1)].

5.5 Eosinophilic Conditions
Patients with asthma on therapy with SINGULAIR 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 events have been sometimes associated with the reduction of oral corticosteroid therapy. Physicians should be alert to eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy presenting in their patients. A causal association between SINGULAIR and these underlying conditions has not been established [see Adverse Reactions (6.2)].

5.6 Risk in Patients with Phenylketonuria
SINGULAIR contains aspartame, a source of phenylalanine. Phenylalanine can be harmful to patients with phenylketonuria (PKU). Each 4 mg and 5 mg chewable tablet contains 0.674 mg and 0.842 mg of phenylalanine, respectively. Before prescribing SINGULAIR to a patient with PKU, consider the combined daily amount of phenylalanine from all sources, including SINGULAIR.


6      ADVERSE REACTIONS
The following clinically significant adverse reactions are described elsewhere in the labeling: • Neuropsychiatric Events [see Warnings and Precautions (5.1)]

6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. In the following description of clinical trials experience, adverse reactions are listed regardless of causality assessment.

The most common adverse reactions (incidence ≥5% and greater than placebo; listed in descending order of frequency) in controlled clinical trials were: upper respiratory infection, fever, headache, pharyngitis, cough, abdominal pain, diarrhea, otitis media, influenza, rhinorrhea, sinusitis, otitis.

Adults and Adolescents 15 Years of Age and Older with Asthma
SINGULAIR has been evaluated for safety in approximately 2950 adult and adolescent patients 15 years of age and older in clinical trials. In placebo-controlled clinical trials, the following adverse reactions reported with SINGULAIR occurred in greater than or equal to 1% of patients and at an incidence greater than that in patients treated with placebo:

Table 5: Adverse Reactions Occurring in 1% of Patients with an Incidence Greater than that in Patients Treated with
Placebo

SINGULAIR          Placebo
10 mg/day
(%)             (%)
(n=1955)        (n=1180)
Body As A Whole
Pain, abdominal                          2.9              2.5
Asthenia/fatigue                         1.8              1.2
Fever                                    1.5              0.9
Trauma                                   1.0              0.8
Digestive System Disorders
Dyspepsia                               2.1              1.1
Pain, dental                            1.7              1.0
Gastroenteritis, infectious             1.5              0.5

Nervous System/Psychiatric
Headache                                18.4             18.1
Dizziness                                1.9              1.4

Respiratory System Disorders
Influenza                                4.2              3.9
Cough                                    2.7              2.4
Congestion, nasal                        1.6              1.3
Skin/Skin Appendages Disorder
Rash                                    1.6              1.2
Laboratory Adverse Reactions*
ALT increased                            2.1              2.0
AST increased                            1.6              1.2
Pyuria                                   1.0              0.9
* Number of patients tested (SINGULAIR and placebo, respectively): ALT and AST, 1935, 1170; pyuria, 1924, 1159.

The frequency of less common adverse reactions was comparable between SINGULAIR and placebo.


Cumulatively, 569 patients were treated with SINGULAIR for at least 6 months, 480 for one year, and 49 for two years in clinical trials. With prolonged treatment, the adverse reaction profile did not significantly change.

Pediatric Patients 6 to 14 Years of Age with Asthma
SINGULAIR has been evaluated for safety in 476 pediatric patients 6 to 14 years of age. Cumulatively, 289 pediatric patients were treated with SINGULAIR for at least 6 months, and 241 for one year or longer in clinical trials. The safety profile of SINGULAIR in the 8-week, double-blind, pediatric efficacy trial was generally similar to the adult safety profile. In pediatric patients 6 to 14 years of age receiving SINGULAIR, the following reactions occurred with a frequency 2% and more frequently than in pediatric patients who received placebo: pharyngitis, influenza, fever, sinusitis, nausea, diarrhea, dyspepsia, otitis, viral infection, and laryngitis. The frequency of less common adverse reactions was comparable between SINGULAIR and placebo. With prolonged treatment, the adverse reaction profile did not significantly change.

In studies evaluating growth rate, the safety profile in these pediatric patients was consistent with the safety profile previously described for SINGULAIR. In a 56-week, double-blind study evaluating growth rate in pediatric patients 6 to 8 years of age receiving SINGULAIR, the following reactions not previously observed with the use of SINGULAIR in this age group occurred with a frequency 2% and more frequently than in pediatric patients who received placebo: headache, rhinitis (infective), varicella, gastroenteritis, atopic dermatitis, acute bronchitis, tooth infection, skin infection, and myopia.

Pediatric Patients 2 to 5 Years of Age with Asthma
SINGULAIR has been evaluated for safety in 573 pediatric patients 2 to 5 years of age in single- and multiple-dose studies. Cumulatively, 426 pediatric patients 2 to 5 years of age were treated with SINGULAIR for at least 3 months, 230 for 6 months or longer, and 63 patients for one year or longer in clinical trials. In pediatric patients 2 to 5 years of age receiving SINGULAIR, the following reactions occurred with a frequency 2% and more frequently than in pediatric patients who received placebo: fever, cough, abdominal pain, diarrhea, headache, rhinorrhea, sinusitis, otitis, influenza, rash, ear pain, gastroenteritis, eczema, urticaria, varicella, pneumonia, dermatitis, and conjunctivitis.

Pediatric Patients 6 to 23 Months of Age with Asthma
Safety and effectiveness in pediatric patients younger than 12 months of age with asthma have not been established.

SINGULAIR has been evaluated for safety in 175 pediatric patients 6 to 23 months of age. The safety profile of SINGULAIR in a 6-week, double-blind, placebo-controlled clinical study was generally similar to the safety profile in adults and pediatric patients 2 to 14 years of age. In pediatric patients 6 to 23 months of age receiving SINGULAIR, the following reactions occurred with a frequency 2% and more frequently than in pediatric patients who received placebo: upper respiratory infection, wheezing; otitis media; pharyngitis, tonsillitis, cough; and rhinitis. The frequency of less common adverse reactions was comparable between SINGULAIR and placebo.

Adults and Adolescents 15 Years of Age and Older with Seasonal Allergic Rhinitis SINGULAIR has been evaluated for safety in 2199 adult and adolescent patients 15 years of age and older in clinical trials. SINGULAIR administered once daily in the morning or in the evening had a safety profile similar to that of placebo. In placebo-controlled clinical trials, the following reaction was reported with SINGULAIR with a frequency 1% and at an incidence greater than placebo: upper respiratory infection, 1.9% of patients receiving SINGULAIR vs. 1.5% of patients receiving placebo. In a 4-week, placebo- controlled clinical study, the safety profile was consistent with that observed in 2-week studies. The incidence of somnolence was similar to that of placebo in all studies.

Pediatric Patients 2 to 14 Years of Age with Seasonal Allergic Rhinitis SINGULAIR has been evaluated in 280 pediatric patients 2 to 14 years of age in a 2-week, multicenter, double-blind, placebo-controlled, parallel-group safety study. SINGULAIR administered once daily in the evening had a safety profile similar to that of placebo. In this study, the following reactions occurred with a 
frequency 2% and at an incidence greater than placebo: headache, otitis media, pharyngitis, and upper respiratory infection.

6.2 Postmarketing Experience
The following adverse reactions have been identified during post-approval use of SINGULAIR. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Blood and lymphatic system disorders increased bleeding tendency, thrombocytopenia

Immune system disorders hypersensitivity reactions including anaphylaxis, hepatic eosinophilic infiltration 
Psychiatric disorders including, but not limited to, agitation, aggressive behavior or hostility, anxiousness, depression, disorientation, disturbance in attention, dream abnormalities, dysphemia (stuttering), hallucinations, insomnia, irritability, memory impairment, obsessive-compulsive symptoms, restlessness, somnambulism, suicidal thinking and behavior (including suicide), tic, and tremor [see Boxed Warning, Warnings and Precautions (5.1)]

Nervous system disorders drowsiness, paraesthesia/hypoesthesia, seizures

Cardiac disorders palpitations
Respiratory, thoracic and mediastinal disorders epistaxis, pulmonary eosinophilia

Gastrointestinal disorders diarrhea, dyspepsia, nausea, pancreatitis, vomiting

Hepatobiliary disorders
Cases of cholestatic hepatitis, hepatocellular liver-injury, and mixed-pattern liver injury have been reported in patients treated with SINGULAIR. Most of these occurred in combination with other confounding factors, such as use of other medications, or when SINGULAIR was administered to patients who had underlying potential for liver disease such as alcohol use or other forms of hepatitis.

Skin and subcutaneous tissue disorders angioedema, bruising, erythema multiforme,             erythema     nodosum,     pruritus,   Stevens-Johnson syndrome/toxic epidermal necrolysis, urticaria

Musculoskeletal and connective tissue disorders arthralgia, myalgia including muscle cramps

Renal and urinary disorders enuresis in children
General disorders and administration site conditions edema

Patients with asthma on therapy with SINGULAIR 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 reactions have been sometimes associated with the reduction of oral corticosteroid therapy. Physicians should be alert to eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy presenting in their patients [see Warnings and Precautions (5.5)].

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.
Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form: https://sideeffects.health.gov.il 

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