Montelukast

1.1 Asthma

Montelukast sodium tablets are indicated for the prophylaxis and chronic treatment of asthma in adults and pediatric patients 15 years of age and older.

1.2 Exercise-Induced Bronchoconstriction (EIB)

Montelukast sodium tablets are indicated for prevention of exercise-induced bronchoconstriction (EIB) in patients 15 years of age and older.

1.3 Allergic Rhinitis

Montelukast sodium tablets are indicated for the relief of symptoms of seasonal allergic rhinitis in patients 15 years of age and older and perennial allergic rhinitis in patients 15 years of age and older. Because the benefits of Montelukast Sodium tablet may not outweigh the risk of neuropsychiatric symptoms in patients with allergic rhinitis [see Warnings and Precautions (5.1)], reserve use for patients who have an inadequate response or intolerance to alternative therapies.

1.4 Limitations of Use

Montelukast sodium tablets are not indicated for the treatment of an acute asthma attack.

2.1 Asthma

For asthma, administer Montelukast sodium tablets orally once daily in the evening, with or without food. There have been no clinical trials in patients with asthma to evaluate the relative efficacy of morning versus evening dosing.
The following doses are recommended:
For adults and adolescents 15 years of age and older: one 10 mg tablet.
Patients who miss a dose should take the next dose at their regular time and should not take 2 doses at the same time.

2.2 Exercise-Induced Bronchoconstriction (EIB)

For prevention of EIB, administer a single dose of Montelukast Sodium tablets orally at least 2 hours, before exercise. The following doses are recommended:

For adults and adolescents 15 years of age and older: One 10 mg tablet.

An additional dose of montelukast sodium tablets should not be taken within 24 hours of a previous dose. Patients already taking montelukast sodium tablets daily for another indication (including chronic asthma) should not take an additional dose to prevent EIB. All patients should have available for rescue a short-acting β-agonist.

Daily administration of montelukast sodium tablets for the chronic treatment of asthma has not been established to prevent acute episodes of EIB.

2.3 Allergic Rhinitis

For allergic rhinitis, administer montelukast sodium tablets orally once daily without regard to time of food ingestion. Time of administration in patients with allergic rhinitis can be individualized to suit patient needs.

The following doses for the treatment of symptoms of seasonal allergic rhinitis are recommended:

For adults and adolescents 15 years of age and older: one 10-mg tablet.

The following doses for the treatment of symptoms of perennial allergic rhinitis are recommended:

For adults and adolescents 15 years of age and older: one 10-mg tablet.
Patients who miss a dose should take the next dose at their regular time and should not take 2 doses at the same time.

2.4 Asthma and Allergic Rhinitis

For patients with both asthma and allergic rhinitis, administer only one montelukast sodium tablets dose daily in the evening.

Patients who miss a dose should take the next dose at their regular time and should not take 2 doses at the same time.

Montelukast Sodium Tablets USP, 10 mg are yellow, round, film-coated tablets debossed with 10 on one side and plain on the other.

• Hypersensitivity to any component of this product.

5.1 Neuropsychiatric Events

Serious neuropsychiatric (NP) events have been reported with use of Montelukast Sodium. 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 Montelukast Sodium treatment, but some were reported after Montelukast Sodium discontinuation. Animal studies showed that montelukast distributes into the brain in rats [see Clinical Pharmacology (12.3)]; however, the mechanisms underlying Montelukast Sodium-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 Montelukast Sodium use.
Because of the risk of NP events, the benefits of Montelukast Sodium 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 Montelukast Sodium 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 Montelukast Sodium.
Discuss the benefits and risks of Montelukast Sodium use with patients and caregivers when prescribing Montelukast Sodium. Advise patients and/or caregivers to be alert for changes in behavior or for new NP symptoms when taking Montelukast Sodium. If changes in behavior are observed, or if new NP symptoms or suicidal thoughts and/or behavior occur, advise patients to discontinue Montelukast Sodium and contact a healthcare provider immediately. In many cases, symptoms resolved after stopping Montelukast Sodium therapy; however, in some cases symptoms persisted after discontinuation of Montelukast Sodium. Therefore, continue to monitor and provide supportive care until symptoms resolve. Re-evaluate the benefits and risks of restarting treatment with Montelukast Sodium if such events occur.

5.2 Acute Asthma

Montelukast sodium 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 Montelukast Sodium 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, Montelukast Sodium 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 Montelukast Sodium. Although Montelukast Sodium 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 aspirinsensitive asthmatic patients [see Clinical Studies (14.1)] .

5.5 Eosinophilic Conditions

Patients with asthma on therapy with Montelukast Sodium 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 Montelukast Sodium and these underlying conditions has not been established [see Adverse Reactions (6.2)] .

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

Montelukast sodium 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 Montelukast Sodium occurred in greater than or equal to 1% of patients and at an incidence greater than that in patients treated with placebo:

• ¹

^* Number of patients tested (Monelukast Sodium and placebo, respectively): ALT and AST, 1935, 1170; pyuria, 1924, 1159.

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

The safety profile of Montelukast Sodium, 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 Montelukast Sodium.

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

Adults and Adolescents 15 Years of Age and Older with Seasonal Allergic Rhinitis

Montelukast sodium has been evaluated for safety in 2,199 adult and adolescent patients 15 years of age and older in clinical trials. Montelukast sodium 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 Montelukast Sodium with a frequency ≥ 1% and at an incidence greater than placebo: upper respiratory infection, 1.9% of patients receiving Montelukast Sodium 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.

Adults and Adolescents 15 Years of Age and Older with Perennial Allergic Rhinitis

Montelukast Sodium 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 Montelukast Sodium in two, 6-week, clinical studies. Montelukast Sodium 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 reactions were reported with Montelukast Sodium 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.

6.2 Post-Marketing Experience

The following adverse reactions have been identified during post-approval use of Montelukast Sodium. 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 Montelukast Sodium. Most of these occurred in combination with other confounding factors, such as use of other medications, or when Montelukast Sodium 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 Montelukast Sodium 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)].

No dose adjustment is needed when Montelukast Sodium is co-administered with theophylline, prednisone, prednisolone, oral contraceptives, fexofenadine, digoxin, warfarin, gemfibrozil, itraconazole, thyroid hormones, sedative hypnotics, non-steroidal anti-inflammatory agents, benzodiazepines, decongestants, and Cytochrome P450 (CYP) enzyme inducers [see Clinical Pharmacology (12.3)].

8.1 Pregnancy

Risk Summary

Available data from published prospective and retrospective cohort studies over decades with montelukast use in pregnant women have not established a drug-associated risk of major birth defects [see Data]. In animal reproduction studies, no adverse developmental effects were observed with oral administration of montelukast to pregnant rats and rabbits during organogenesis at doses approximately 100 and 110 times, respectively, the maximum recommended human daily oral dose (MRHDOD) based on AUCs [see Data].
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Clinical Considerations

Disease-associated maternal and/or embryo/fetal risk

Poorly or moderately controlled asthma in pregnancy increases the maternal risk of perinatal adverse outcomes such as preeclampsia and infant prematurity, low birth weight, and small for gestational age.

Data

Human Data

Published data from prospective and retrospective cohort studies have not identified an association with Montelukast Sodium use during pregnancy and major birth defects.
Available studies have methodologic limitations, including small sample size, in some cases retrospective data collection, and inconsistent comparator groups.

Animal Data

In embryo-fetal development studies, montelukast administered to pregnant rats and rabbits during organogenesis (gestation days 6 to 17 in rats and 6 to 18 in rabbits) did not cause any adverse developmental effects at maternal oral doses up to 400 and 300 mg/kg/day in rats and rabbits, respectively (approximately 100 and 110 times the AUC in humans at the MRHDOD, respectively).

8.2 Lactation

Risk Summary

A published clinical lactation study reports the presence of montelukast in human milk. Data available on the effects of the drug on infants, either directly [see Use in Specific Populations (8.4)] or through breast milk, do not suggest a significant risk of adverse reactions from exposure to Montelukast Sodium. The effects of the drug on milk production are unknown. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Montelukast Sodium and any potential adverse reactions on the breastfed infant from Montelukast Sodium or from the underlying maternal condition.

8.4 Pediatric Use

The safety and effectiveness in pediatric patients below the age of 12 months with asthma, 6 months with perennial allergic rhinitis, and 6 years with exercise-induced bronchoconstriction have not been established.

8.5 Geriatric Use

Of the total number of subjects in clinical studies of montelukast, 3.5% were 65 years of age and over, and 0.4% were 75 years of age and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. The pharmacokinetic profile and the oral bioavailability of a single 10-mg oral dose of montelukast are similar in elderly and younger adults. The plasma half-life of montelukast is slightly longer in the elderly. No dosage adjustment in the elderly is required.

8.6 Hepatic Impairment

No dosage adjustment is required in patients with mild-to-moderate hepatic insufficiency [see Clinical Pharmacology (12.3)] .

8.7 Renal Impairment

No dosage adjustment is recommended in patients with renal insufficiency [see Clinical Pharmacology (12.3)].

No specific information is available on the treatment of overdosage with Montelukast Sodium. In the event of overdose, it is reasonable to employ the usual supportive measures; e.g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring, and institute supportive therapy, if required. It is not known whether montelukast is removed by peritoneal dialysis or hemodialysis.

12.1 Mechanism of Action

The cysteinyl leukotrienes (LTC ₄, LTD ₄, LTE ₄) are products of arachidonic acid metabolism and are released from various cells, including mast cells and eosinophils. These eicosanoids bind to cysteinyl leukotriene (CysLT) receptors. The CysLT type-1 (CysLT ₁) receptor is found in the human airway (including airway smooth muscle cells and airway macrophages) and on other proinflammatory cells (including eosinophils and certain myeloid stem cells). CysLTs have been correlated with the pathophysiology of asthma and allergic rhinitis. In asthma, leukotriene-mediated effects include airway edema, smooth muscle contraction, and altered cellular activity associated with the inflammatory process. In allergic rhinitis, CysLTs are released from the nasal mucosa after allergen exposure during both early- and late-phase reactions and are associated with symptoms of allergic rhinitis.

Montelukast is an orally active compound that binds with high affinity and selectivity to the CysLT ₁ receptor (in preference to other pharmacologically important airway receptors, such as the prostanoid, cholinergic, or β-adrenergic receptor). Montelukast inhibits physiologic actions of LTD ₄ at the CysLT ₁ receptor without any agonist activity.

12.2 Pharmacodynamics

Montelukast causes inhibition of airway cysteinyl leukotriene receptors as demonstrated by the ability to inhibit bronchoconstriction due to inhaled LTD ₄ in asthmatics. Doses as low as 5 mg cause substantial blockage of LTD ₄-induced bronchoconstriction. In a placebo-controlled, crossover study (n = 12), Montelukast Sodium inhibited early- and late-phase bronchoconstriction due to antigen challenge by 75% and 57%, respectively.

The effect of Montelukast Sodium on eosinophils in the peripheral blood was examined in clinical trials. In patients with asthma aged 2 years and older who received Montelukast Sodium, a decrease in mean peripheral blood eosinophil counts ranging from 9% to 15% was noted, compared with placebo, over the double-blind treatment periods. In patients with seasonal allergic rhinitis aged 15 years and older who received Montelukast Sodium, a mean increase of 0.2% in peripheral blood eosinophil counts was noted, compared with a mean increase of 12.5% in placebo-treated patients, over the double-blind treatment periods; this reflects a mean difference of 12.3% in favor of Montelukast Sodium. The relationship between these observations and the clinical benefits of montelukast noted in the clinical trials is not known [see Clinical Studies (14)].

12.3 Pharmacokinetics

Absorption

Montelukast is rapidly absorbed following oral administration. After administration of the 10-mg film-coated tablet to fasted adults, the mean peak montelukast plasma concentration (C _max) is achieved in 3 to 4 hours (T _max). The mean oral bioavailability is 64%. The oral bioavailability and C _max are not influenced by a standard meal in the morning.

The safety and effectiveness of Montelukast Sodium in patients with asthma were demonstrated in clinical trials in which the 10-mg film-coated tablet was administered in the evening without regard to the time of food ingestion. The safety and effectiveness of Montelukast Sodium in patients with seasonal allergic rhinitis were demonstrated in clinical trials in which the 10-mg film-coated tablet was administered in the morning or evening without regard to the time of food ingestion.

The comparative pharmacokinetics of montelukast when administered as two 5-mg chewable tablets versus one 10-mg film-coated tablet have not been evaluated.

Distribution

Montelukast is more than 99% bound to plasma proteins. The steady state volume of distribution of montelukast averages 8 to 11 liters. Orally administered montelukast distributes into the brain in rats.

Elimination

The plasma clearance of montelukast averages 45 mL/min in healthy adults. Following an oral dose of radiolabeled montelukast, 86% of the radioactivity was recovered in 5-day fecal collections and <0.2% was recovered in urine. Coupled with estimates of montelukast oral bioavailability, this indicates that montelukast and its metabolites are excreted almost exclusively via the bile.

In several studies, the mean plasma half-life of montelukast ranged from 2.7 to 5.5 hours in healthy young adults. The pharmacokinetics of montelukast are nearly linear for oral doses up to 50 mg. During once-daily dosing with 10-mg montelukast, there is little accumulation of the parent drug in plasma (14%).

Metabolism

Montelukast is extensively metabolized. In studies with therapeutic doses, plasma concentrations of metabolites of montelukast are undetectable at steady state in adults and pediatric patients.

In vitro studies using human liver microsomes indicate that CYP3A4, 2C8, and 2C9 are involved in the metabolism of montelukast. At clinically relevant concentrations, 2C8 appears to play a major role in the metabolism of montelukast.

Specific Populations

Patients with Hepatic Impairment

Patients with mild-to-moderate hepatic insufficiency and clinical evidence of cirrhosis had evidence of decreased metabolism of montelukast resulting in 41% (90% CI=7%, 85%) higher mean montelukast AUC following a single 10-mg dose. The elimination of montelukast was slightly prolonged compared with that in healthy subjects (mean half-life, 7.4 hours). No dosage adjustment is required in patients with mild-to-moderate hepatic insufficiency. The pharmacokinetics of Montelukast Sodium in patients with more severe hepatic impairment or with hepatitis have not been evaluated.

Patients with Renal Insufficiency

Since montelukast and its metabolites are not excreted in the urine, the pharmacokinetics of montelukast were not evaluated in patients with renal insufficiency. No dosage adjustment is recommended in these patients.

Male and Female Patients

The pharmacokinetics of montelukast are similar in males and females.

Racial Groups

Pharmacokinetic differences due to race have not been studied.

Adolescents

Pharmacokinetic studies evaluated the systemic exposure of the 10-mg film-coated tablets in young adults and adolescents ≥15 years of age.

The plasma concentration profile of montelukast following administration of the 10-mg film-coated tablet is similar in adolescents ≥15 years of age and young adults. The 10-mg film-coated tablet is recommended for use in patients ≥15 years of age.

Drug Interaction Studies

Theophylline, Prednisone, and Prednisolone

Montelukast Sodium has been administered with other therapies routinely used in the prophylaxis and chronic treatment of asthma with no apparent increase in adverse reactions. In drug-interaction studies, the recommended clinical dose of montelukast did not have clinically important effects on the pharmacokinetics of the following drugs: theophylline, prednisone, and prednisolone.

Montelukast at a dose of 10 mg once daily dosed to pharmacokinetic steady state, did not cause clinically significant changes in the kinetics of a single intravenous dose of theophylline [predominantly a cytochrome P450 (CYP) 1A2 substrate]. Montelukast at doses of ≥100 mg daily dosed to pharmacokinetic steady state, did not cause any clinically significant change
in plasma profiles of prednisone or prednisolone following administration of either oral prednisone or intravenous prednisolone.

Oral Contraceptives, Fexofenadine , Digoxin, and Warfarin

In drug interaction studies, the recommended clinical dose of montelukast did not have clinically important effects on the pharmacokinetics of the following drugs: oral contraceptives (norethindrone 1 mg/ethinyl estradiol 35 mcg), digoxin, and warfarin. Montelukast at doses of ≥100 mg daily dosed to pharmacokinetic steady state did not significantly alter the plasma concentrations of either component of an oral contraceptive containing norethindrone 1 mg/ethinyl estradiol 35 mcg. Montelukast at a dose of 10 mg once daily dosed to pharmacokinetic steady state did not change the plasma concentration profile of fexofenadine (a substrate of CYP3A4) or fexofenadine, did not change the pharmacokinetic profile or urinary excretion of immunoreactive digoxin; did not change the pharmacokinetic profile of warfarin (primarily a substrate of CYP2C9, 3A4 and 1A2) or influence the effect of a single 30-mg oral dose of warfarin on prothrombin time or the International Normalized Ratio (INR).

Thyroid Hormones, Sedative Hypnotics, Non-Steroidal Anti-Inflammatory Agents, Benzodiazepines, and Decongestants

Although additional specific interaction studies were not performed, Montelukast Sodium was used concomitantly with a wide range of commonly prescribed drugs in clinical studies without evidence of clinical adverse interactions. These medications included thyroid hormones, sedative hypnotics, non-steroidal anti-inflammatory agents, benzodiazepines, and decongestants.

Cytochrome P450 (CYP) Enzyme Inducers

Phenobarbital, which induces hepatic metabolism, decreased the area under the plasma concentration curve (AUC) of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for Montelukast Sodium is recommended. It is reasonable to employ appropriate clinical monitoring when potent CYP enzyme inducers, such as phenobarbital or rifampin, are co-administered with Montelukast Sodium.

Effect of Montelukast on Cytochrome P450 (CYP) Enzymes

Montelukast is a potent inhibitor of CYP2C8 in vitro. However, data from a clinical drug-drug interaction study involving montelukast and rosiglitazone (a probe substrate representative of drugs primarily metabolized by CYP2C8) in 12 healthy individuals demonstrated that the pharmacokinetics of rosiglitazone are not altered when the drugs are coadministered, indicating that montelukast does not inhibit CYP2C8 in vivo. Therefore, montelukast is not anticipated to alter the metabolism of drugs metabolized by this enzyme (e.g., paclitaxel, rosiglitazone, and repaglinide). Based on further in vitro results in human liver microsomes, therapeutic plasma concentrations of montelukast do not inhibit CYP 3A4, 2C9, 1A2, 2A6, 2C19, or 2D6.

Cytochrome P450 (CYP) Enzyme Inhibitors

In vitro studies have shown that montelukast is a substrate of CYP 2C8, 2C9, and 3A4. Co-administration of montelukast with itraconazole, a strong CYP 3A4 inhibitor, resulted in no significant increase in the systemic exposure of montelukast. Data from a clinical drug-drug interaction study involving montelukast and gemfibrozil (an inhibitor of both CYP 2C8 and 2C9) demonstrated that gemfibrozil, at a therapeutic dose, increased the systemic exposure of montelukast by 4.4-fold. Co-administration of itraconazole, gemfibrozil, and montelukast did not further increase the systemic exposure of montelukast. Based on available clinical experience, no dosage adjustment of montelukast is required upon co-administration with gemfibrozil [see Overdosage (10)]

Montelukast Sodium Tablets USP, 10 mg are yellow, round, film-coated tablets debossed with 10 on one side and plain on the other. They are supplied as follows:

Bottles of 90: NDC 69367-287-09

Bottles of 500: NDC 69367-287-05

Storage

Store 10-mg film-coated tablets at 20°C to 25°C (68°F to 77°F), excursions permitted to 15°C-30°C (59°F-86°F) [see USP Controlled Room Temperature]. Protect from moisture and light. Store in original package.