Side Effects of Singulair (montelukast)

Singulair (montelukast) is an oral leukotriene receptor antagonist used to treat asthma and seasonal allergic rhinitis (hay fever). 

Leukotrienes are a group of naturally occurring chemicals in the body that promote inflammation in asthma and seasonal allergic rhinitis and in other diseases in which inflammation is important (such as allergy). They are formed by cells, released, and then bound to other cells that cause inflammation. It is the binding to other cells that stimulates the cells to cause inflammation. 

Singulair works in a manner similar to zafirlukast, blocking the binding of some leukotrienes to the cells that cause inflammation. Unlike zafirlukast, Singulair does not inhibit CYP2C9 or CYP3A4, two enzymes in the liver that are important in breaking down and eliminating many drugs. 

Therefore, unlike zafirlukast, Singulair is not expected to affect the elimination of other drugs. The safety and effectiveness of montelukast has been demonstrated in children as young as 6 months of age. 

Common side effects of Singulair include

• headache,
• dizziness,
• abdominal pain,
• sore throat,
• runny nose,
• wheezing,
• cough,
• rash,
• restlessness,
• tremor, and
• nausea.

Serious side effects of Singulair include

• elevated liver enzymes,
• suicidal behavior,
• fluid retention,
• depression, and
• hallucinations.

Drug interactions of Singulair include phenobarbital, rifampin, and carbamazepine, which may decrease blood concentrations of Singulair, and may reduce the effect of Singulair. 

There have been no adequate studies of Singulair in pregnant women to determine the effects on the fetus. 

It is unknown if Singulair is secreted into human breast milk. Consult your doctor before breastfeeding.

The most common side effects with montelukast are:

• headache,
• dizziness,
• abdominal pain,
• sore throat, and
• rhinitis (inflammation of the inner lining of the nose).

Other important side effects include:

• wheezing,
• cough,
• rash,
• restlessness,
• tremor, and
• nausea.

Elevated liver enzymes, suicidal behavior, fluid retention, depression, and hallucinations have also been reported.

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 experiences 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 1: Adverse Experiences Occurring in ≥1% of Patients with an Incidence Greater than that in Patients Treated with Placebo

The frequency of less common adverse events was comparable between Singulair and placebo.

The safety profile of Singulair, when administered as a single dose for prevention of EIB in adult and adolescent patients 15 years of age and older, was consistent with the safety profile previously described for Singulair.

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 experience 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 events 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 events was comparable between Singulair and placebo. With prolonged treatment, the adverse experience profile did not significantly change.

The safety profile of Singulair, when administered as a single dose for prevention of EIB in pediatric patients 6 years of age and older, was consistent with the safety profile previously described for Singulair.

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 events 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 events 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 events 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 events 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 event 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 events occurred with a frequency ≥2% and at an incidence greater than placebo:

• headache,
• otitis media,
• pharyngitis, and
• upper respiratory infection.

Adults And Adolescents 15 Years Of Age And Older With Perennial Allergic Rhinitis

Singulair has been evaluated for safety in 3357 adult and adolescent patients 15 years of age and older with perennial allergic rhinitis of whom 1632 received Singulair in two, 6-week, clinical studies. Singulair administered once daily had a safety profile consistent with that observed in patients with seasonal allergic rhinitis and similar to that of placebo.

In these two studies, the following events were reported with Singulair with a frequency ≥1% and at an incidence greater than placebo:

• sinusitis,
• upper respiratory infection,
• sinus headache,
• cough,
• epistaxis, and
• increased ALT.

The incidence of somnolence was similar to that of placebo.

Pediatric Patients 6 Months To 14 Years Of Age With Perennial Allergic Rhinitis

The safety in patients 2 to 14 years of age with perennial allergic rhinitis is supported by the safety in patients 2 to 14 years of age with seasonal allergic rhinitis. The safety in patients 6 to 23 months of age is supported by data from pharmacokinetic and safety and efficacy studies in asthma in this pediatric population and from adult pharmacokinetic studies.

Post-Marketing 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.

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 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.

No dose adjustment is needed when Singulair is co-administered with

• theophylline,
• prednisone,
• prednisolone,
• oral contraceptives,
• terfenadine,
• digoxin,
• warfarin,
• gemfibrozil,
• itraconazole,
• thyroid hormones,
• sedative hypnotics,
• non-steroidal anti-inflammatory agents,
• benzodiazepines,
• decongestants, and
• Cytochrome P450 (CYP) enzyme inducers.