Mondeslor

Desloratadine:

• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Drug interactions
• Use in specific populations
• Drug abuse and dependence
• Overdosage
• Description
• Clinical pharmacology
• Nonclinical toxicology
• Clinical studies
• How supplied/storage and handling
• Patient counseling information
• Mondeslor (Desloratadine) reviews

1 INDICATIONS AND USAGE

Mondeslor Tablets are indicated for:

• Seasonal Allergic Rhinitis: relief of nasal and non-nasal symptoms in patients 12 years of age and older. (1.1)
• Perennial Allergic Rhinitis: relief of nasal and non-nasal symptoms in patients 12 years of age and older. (1.2)
• Chronic Idiopathic Urticaria: symptomatic relief of pruritus reduction in the number of hives, and size of hives in patients 12 years of age and older. (1.3)

1.1 Seasonal Allergic Rhinitis

Mondeslor (Desloratadine) Tablets are indicated for the relief of the nasal and non-nasal symptoms of seasonal allergic rhinitis in patients 12 years of age and older.

1.2 Perennial Allergic Rhinitis

Mondeslor Tablets are indicated for the relief of the nasal and non-nasal symptoms of perennial allergic rhinitis in patients 12 years of age and older.

1.3 Chronic Idiopathic Urticaria

Mondeslor (Desloratadine) Tablets are indicated for the symptomatic relief of pruritus, reduction in the number of hives, and size of hives, in patients with chronic idiopathic urticaria 12 years of age and older.

2 DOSAGE AND ADMINISTRATION

Mondeslor Tablets may be taken without regard to meals.

Dosage (by age):

Adults and adolescents 12 years of age and over:

• Mondeslor (Desloratadine) Tablets - one 5 mg tablet once daily

2.1 Adults and adolescents 12 years of age and over

The recommended dose of Mondeslor (Desloratadine) Tablets is one 5 mg tablet once daily.

2.5 Adults with Hepatic or Renal Impairment

In adult patients with liver or renal impairment, a starting dose of one 5 mg tablet every other day is recommended based on pharmacokinetic data. Dosing recommendation for children with liver or renal impairment cannot be made due to lack of data [see Clinical Pharmacology (12.3) ].

3 DOSAGE FORMS AND STRENGTHS

Mondeslor (Desloratadine) Tablets are light blue round tablets debossed with "5" containing 5 mg Mondeslor (Desloratadine).

• Mondeslor (Desloratadine) Tablets - 5 mg (3)

4 CONTRAINDICATIONS

Mondeslor (Desloratadine) Tablets are contraindicated in patients who are hypersensitive to this medication or to any of its ingredients or to loratadine [see Warnings and Precautions (5.1) and Adverse Reactions (6.2) ].

• Hypersensitivity (4, 6.2)

5 WARNINGS AND PRECAUTIONS

• Hypersensitivity reactions including rash, pruritus, urticaria, edema, dyspnea, and anaphylaxis have been reported. In such cases, stop Mondeslor Tablets at once and consider alternative treatments. (5.1)

5.1 Hypersensitivity Reactions

Hypersensitivity reactions including rash, pruritus, urticaria, edema, dyspnea, and anaphylaxis have been reported after administration of Mondeslor (Desloratadine). If such a reaction occurs, therapy with Mondeslor (Desloratadine) Tablets should be stopped and alternative treatment should be considered. [See Adverse Reactions (6.2) .]

6 ADVERSE REACTIONS

The following adverse reactions are discussed in greater detail in other sections of the label:

• Hypersensitivity reactions. [See Warnings and Precautions .]

• The most common adverse reactions (reported in ≥2% of adult and adolescent patients with allergic rhinitis and greater than placebo) were pharyngitis, dry mouth, myalgia, fatigue, somnolence, dysmenorrhea. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Virtus Pharmaceuticals at 813-283-1344 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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.

Adults and Adolescents

Allergic Rhinitis: In multiple-dose placebo-controlled trials, 2,834 patients ages 12 years or older received Mondeslor (Desloratadine) Tablets at doses of 2.5 mg to 20 mg daily, of whom 1,655 patients received the recommended daily dose of 5 mg. In patients receiving 5 mg daily, the rate of adverse events was similar between Mondeslor (Desloratadine) and placebo-treated patients. The percent of patients who withdrew prematurely due to adverse events was 2.4% in the Mondeslor (Desloratadine) group and 2.6% in the placebo group. There were no serious adverse events in these trials in patients receiving Mondeslor (Desloratadine). All adverse events that were reported by greater than or equal to 2% of patients who received the recommended daily dose of Mondeslor (Desloratadine) Tablets (5 mg once daily), and that were more common with Mondeslor (Desloratadine) Tablets than placebo, are listed in Table 1.

The frequency and magnitude of laboratory and electrocardiographic abnormalities were similar in Mondeslor (Desloratadine) and placebo-treated patients. There were no differences in adverse events for subgroups of patients as defined by gender, age, or race.

Chronic Idiopathic Urticaria: In multiple-dose, placebo-controlled trials of chronic idiopathic urticaria, 211 patients ages 12 years or older received Mondeslor (Desloratadine) Tablets and 205 received placebo. Adverse events that were reported by greater than or equal to 2% of patients who received Mondeslor (Desloratadine) Tablets and that were more common with Mondeslor (Desloratadine) than placebo were (rates for Mondeslor (Desloratadine) and placebo, respectively): headache (14%, 13%), nausea (5%, 2%), fatigue (5%, 1%), dizziness (4%, 3%), pharyngitis (3%, 2%), dyspepsia (3%, 1%), and myalgia (3%, 1%).

Pediatrics: Two hundred and forty-six pediatric subjects 6 months to 11 years of age received Mondeslor (Desloratadine) Oral Solution for 15 days in three placebo controlled clinical trials. Pediatric subjects aged 6 to 11 years received 2.5 mg once a day, subjects aged 1 to 5 years received 1.25 mg once a day, and subjects 6 to 11 months of age received 1.0 mg once a day.

In subjects 6 to 11 years of age, no individual adverse event was reported by 2 percent or more of the subjects.

In subjects 2 to 5 years of age, adverse events reported for Mondeslor (Desloratadine) and placebo in at least 2 percent of subjects receiving Mondeslor (Desloratadine) Oral Solution and at a frequency greater than placebo were fever (5.5%, 5.4%), urinary tract infection (3.6%, 0%) and varicella (3.6%, 0%).

In subjects 12 months to 23 months of age, adverse events reported for the Mondeslor (Desloratadine) product and placebo in at least 2 percent of subjects receiving Mondeslor (Desloratadine) Oral Solution and at a frequency greater than placebo were fever (16.9%, 12.9%), diarrhea (15.4%, 11.3%), upper respiratory tract infections (10.8%, 9.7%), coughing (10.8%, 6.5%), appetite increased (3.1%, 1.6%), emotional lability (3.1%, 0%), epistaxis (3.1%, 0%), parasitic infection (3.1%, 0%), pharyngitis (3.1%, 0%), rash maculopapular (3.1%, 0%).

In subjects 6 months to 11 months of age, adverse events reported for Mondeslor (Desloratadine) and placebo in at least 2 percent of subjects receiving Mondeslor (Desloratadine) Oral Solution and at a frequency greater than placebo were upper respiratory tract infections (21.2%, 12.9%), diarrhea (19.7%, 8.1%), fever (12.1%, 1.6%), irritability (12.1%, 11.3%), coughing (10.6%, 9.7%), somnolence (9.1%, 8.1%), bronchitis (6.1%, 0%), otitis media (6.1%, 1.6%), vomiting (6.1%, 3.2%), anorexia (4.5%, 1.6%), pharyngitis (4.5%, 1.6%), insomnia (4.5%, 0%), rhinorrhea (4.5%, 3.2%), erythema (3.0%, 1.6%), and nausea (3.0%, 0%). There were no clinically meaningful changes in any electrocardiographic parameter, including the QTc interval. Only one of the 246 pediatric subjects receiving Mondeslor (Desloratadine) Oral Solution in the clinical trials discontinued treatment because of an adverse event.

6.2 Post-Marketing Experience

Because adverse events 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. The following spontaneous adverse events have been reported during the marketing of Mondeslor (Desloratadine): tachycardia, palpitations, rare cases of hypersensitivity reactions (such as rash, pruritus, urticaria, edema, dyspnea, and anaphylaxis), psychomotor hyperactivity, seizures, and elevated liver enzymes including bilirubin, and very rarely, hepatitis.

7 DRUG INTERACTIONS

7.1 Inhibitors of Cytochrome P450 3A4

In controlled clinical studies co-administration of Mondeslor with ketoconazole, erythromycin, or azithromycin resulted in increased plasma concentrations of Mondeslor (Desloratadine) and 3 hydroxydesloratadine, but there were no clinically relevant changes in the safety profile of Mondeslor (Desloratadine). [See Clinical Pharmacology (12.3) .]

7.2 Fluoxetine

In controlled clinical studies co-administration of Mondeslor (Desloratadine) with fluoxetine, a selective serotonin reuptake inhibitor (SSRI), resulted in increased plasma concentrations of Mondeslor (Desloratadine) and 3 hydroxydesloratadine, but there were no clinically relevant changes in the safety profile of Mondeslor (Desloratadine). [See Clinical Pharmacology (12.3) .]

7.3 Cimetidine

In controlled clinical studies co-administration of Mondeslor (Desloratadine) with cimetidine, a histamine H₂-receptor antagonist, resulted in increased plasma concentrations of Mondeslor (Desloratadine) and 3 hydroxydesloratadine, but there were no clinically relevant changes in the safety profile of Mondeslor (Desloratadine). [See Clinical Pharmacology (12.3).]

8 USE IN SPECIFIC POPULATIONS

• Renal impairment: dosage adjustment is recommended
• Hepatic impairment: dosage adjustment is recommended (2.5, 8.7, 12.3)

8.1 Pregnancy

Pregnancy Category C: There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, Mondeslor (Desloratadine) should be used during pregnancy only if clearly needed. Mondeslor (Desloratadine) was not teratogenic in rats or rabbits at approximately 210 and 230 times, respectively, the area under the concentration-time curve (AUC) in humans at the recommended daily oral dose. An increase in pre-implantation loss and a decreased number of implantations and fetuses were noted, however, in a separate study in female rats at approximately 120 times the AUC in humans at the recommended daily oral dose. Reduced body weight and slow righting reflex were reported in pups at approximately 50 times or greater than the AUC in humans at the recommended daily oral dose. Mondeslor (Desloratadine) had no effect on pup development at approximately 7 times the AUC in humans at the recommended daily oral dose. The AUCs in comparison referred to the Mondeslor (Desloratadine) exposure in rabbits and the sum of Mondeslor (Desloratadine) and its metabolites exposures in rats, respectively. [See Nonclinical Toxicology (13.2).]

8.3 Nursing Mothers

Mondeslor passes into breast milk; therefore, a decision should be made whether to discontinue nursing or to discontinue Mondeslor (Desloratadine), taking into account the benefit of the drug to the nursing mother and the possible risk to the child.

8.4 Pediatric Use

The recommended dose of Mondeslor (Desloratadine) Oral Solution in the pediatric population is based on cross-study comparison of the plasma concentration of Mondeslor (Desloratadine) in adults and pediatric subjects. The safety of Mondeslor (Desloratadine) Oral Solution has been established in 246 pediatric subjects aged 6 months to 11 years in three placebo-controlled clinical studies. Since the course of seasonal and perennial allergic rhinitis and chronic idiopathic urticaria and the effects of Mondeslor (Desloratadine) are sufficiently similar in the pediatric and adult populations, it allows extrapolation from the adult efficacy data to pediatric patients. The effectiveness of Mondeslor (Desloratadine) Oral Solution in these age groups is supported by evidence from adequate and well-controlled studies of Mondeslor (Desloratadine) Tablets in adults. The safety and effectiveness of Mondeslor (Desloratadine) Tablets or Mondeslor (Desloratadine) Oral Solution have not been demonstrated in pediatric patients less than 6 months of age. [See Clinical Pharmacology (12.3).]

8.5 Geriatric Use

Clinical studies of Mondeslor did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. [See Clinical Pharmacology (12.3).]

8.6 Renal Impairment

Dosage adjustment for patients with renal impairment is recommended [see Dosage and Administration (2.5) and Clinical Pharmacology (12.3) ].

8.7 Hepatic Impairment

Dosage adjustment for patients with hepatic impairment is recommended [see Dosage and Administration (2.5) and Clinical Pharmacology (12.3) ].

9 DRUG ABUSE AND DEPENDENCE

There is no information to indicate that abuse or dependency occurs with Mondeslor (Desloratadine) Tablets.

10 OVERDOSAGE

In the event of overdose, consider standard measures to remove any unabsorbed drug. Symptomatic and supportive treatment is recommended. Mondeslor (Desloratadine) and 3-hydroxydesloratadine are not eliminated by hemodialysis.

Information regarding acute overdosage is limited to experience from post-marketing adverse event reports and from clinical trials conducted during the development of the Mondeslor (Desloratadine) product. In a dose-ranging trial, at doses of 10 mg and 20 mg/day somnolence was reported. In another study, no clinically relevant adverse events were reported in normal male and female volunteers who were given single daily doses of Mondeslor (Desloratadine) 45 mg for 10 days [see Clinical Pharmacology (12.2) ].

Lethality occurred in rats at oral doses of 250 mg/kg or greater (estimated Mondeslor (Desloratadine) and Mondeslor (Desloratadine) metabolite exposures were approximately 120 times the AUC in humans at the recommended daily oral dose). The oral median lethal dose in mice was 353 mg/kg (estimated Mondeslor (Desloratadine) exposures were approximately 290 times the human daily oral dose on a mg/m² basis). No deaths occurred at oral doses up to 250 mg/kg in monkeys (estimated Mondeslor (Desloratadine) exposures were approximately 810 times the human daily oral dose on a mg/m² basis).

11 DESCRIPTION

Mondeslor (Desloratadine) Tablets are light blue, round, tablets containing 5 mg Mondeslor (Desloratadine), an antihistamine, to be administered orally. Mondeslor (Desloratadine) Tablets also contain the following inactive ingredients: microcrystalline cellulose NF, pregelatinized starch NF, croscarmellose sodium NF, talc USP, zinc stearate, USP and FD&C Blue #2 HT 11-14%.

Mondeslor (Desloratadine) is a white to off-white powder that is slightly soluble in water, but very soluble in ethanol and propylene glycol. It has an empirical formula: C₁₉H₁₉ClN₂ and a molecular weight of 310.8. The chemical name is 8-chloro-6,11-dihydro-11-(4-piperdinylidene)-5H-benzo[5,6]cyclohepta[1,2-b]pyridine and has the following structure:

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Mondeslor is a long-acting tricyclic histamine antagonist with selective H₁-receptor histamine antagonist activity. Receptor binding data indicates that at a concentration of 2-3 ng/mL (7 nanomolar), Mondeslor (Desloratadine) shows significant interaction with the human histamine H₁-receptor. Mondeslor (Desloratadine) inhibited histamine release from human mast cells in vitro. Results of a radiolabeled tissue distribution study in rats and a radioligand H₁-receptor binding study in guinea pigs showed that Mondeslor (Desloratadine) did not readily cross the blood brain barrier. The clinical significance of this finding is unknown.

12.2 Pharmacodynamics

Wheal and Flare: Human histamine skin wheal studies following single and repeated 5 mg doses of Mondeslor (Desloratadine) have shown that the drug exhibits an antihistaminic effect by 1 hour; this activity may persist for as long as 24 hours. There was no evidence of histamine-induced skin wheal tachyphylaxis within the Mondeslor (Desloratadine) 5 mg group over the 28-day treatment period. The clinical relevance of histamine wheal skin testing is unknown.

Effects on QTc: Single daily doses of 45 mg were given to normal male and female volunteers for 10 days. All ECGs obtained in this study were manually read in a blinded fashion by a cardiologist. In Mondeslor (Desloratadine) - treated subjects, there was an increase in mean heart rate of 9.2 bpm relative to placebo. The QT interval was corrected for heart rate (QTc) by both the Bazett and Fridericia methods. Using the QTc (Bazett) there was a mean increase of 8.1 msec in Desloratadine-treated subjects relative to placebo. Using QTc (Fridericia) there was a mean increase of 0.4 msec in Mondeslor (Desloratadine) treated subjects relative to placebo. No clinically relevant adverse events were reported.

12.3 Pharmacokinetics

Absorption

Following oral administration of a Mondeslor (Desloratadine) 5 mg tablet once daily for 10 days to normal healthy volunteers, the mean time to maximum plasma concentrations (T_max) occurred at approximately 3 hours post dose and mean steady state peak plasma concentrations (C_max) and AUC of 4 ng/mL and 56.9 ng∙hr/mL were observed, respectively. Neither food nor grapefruit juice had an effect on the bioavailability (C_max and AUC) of Mondeslor (Desloratadine).

The pharmacokinetic profile of Mondeslor (Desloratadine) Oral Solution was evaluated in a three-way crossover study in 30 adult volunteers. A single dose of 10 mL of Mondeslor (Desloratadine) Oral Solution containing 5 mg of Mondeslor (Desloratadine) was bioequivalent to a single dose of 5 mg Mondeslor (Desloratadine) Tablet. Food had no effect on the bioavailability (AUC and C_max) of Mondeslor (Desloratadine) Oral Solution.

Distribution

Mondeslor (Desloratadine) and 3-hydroxydesloratadine are approximately 82% to 87% and 85% to 89% bound to plasma proteins, respectively. Protein binding of Mondeslor (Desloratadine) and 3-hydroxydesloratadine was unaltered in subjects with impaired renal function.

Metabolism

Mondeslor (Desloratadine) (a major metabolite of loratadine) is extensively metabolized to 3-hydroxydesloratadine, an active metabolite, which is subsequently glucuronidated. The enzyme(s) responsible for the formation of 3-hydroxydesloratadine have not been identified. Data from clinical trials indicate that a subset of the general population has a decreased ability to form 3-hydroxydesloratadine, and are poor metabolizers of Mondeslor (Desloratadine). In pharmacokinetic studies (n=3,748), approximately 6% of subjects were poor metabolizers of Mondeslor (Desloratadine) (defined as a subject with an AUC ratio of 3-hydroxydesloratadine to Mondeslor (Desloratadine) less than 0.1, or a subject with a Mondeslor (Desloratadine) half-life exceeding 50 hours). These pharmacokinetic studies included subjects between the ages of 2 and 70 years, including 977 subjects aged 2 to 5 years, 1,575 subjects aged 6 to 11 years, and 1196 subjects aged 12 to 70 years. There was no difference in the prevalence of poor metabolizers across age groups. The frequency of poor metabolizers was higher in Blacks (17%, n=988) as compared to Caucasians (2%, n=1,462) and Hispanics (2%, n=1,063). The median exposure (AUC) to Mondeslor (Desloratadine) in the poor metabolizers was approximately 6-fold greater than in the subjects who are not poor metabolizers. Subjects who are poor metabolizers of Mondeslor (Desloratadine) cannot be prospectively identified and will be exposed to higher levels of Mondeslor (Desloratadine) following dosing with the recommended dose of Mondeslor (Desloratadine). In multidose clinical safety studies, where metabolizer status was identified, a total of 94 poor metabolizers and 123 normal metabolizers were enrolled and treated with Mondeslor (Desloratadine) Oral Solution for 15-35 days. In these studies, no overall differences in safety were observed between poor metabolizers and normal metabolizers. Although not seen in these studies, an increased risk of exposure-related adverse events in patients who are poor metabolizers cannot be ruled out.

Elimination

The mean plasma elimination half-life of Mondeslor (Desloratadine) was approximately 27 hours. C_max and AUC values increased in a dose proportional manner following single oral doses between 5 and 20 mg. The degree of accumulation after 14 days of dosing was consistent with the half-life and dosing frequency. A human mass balance study documented a recovery of approximately 87% of the ¹⁴C-desloratadine dose, which was equally distributed in urine and feces as metabolic products. Analysis of plasma 3-hydroxydesloratadine showed similar T_max and half-life values compared to Mondeslor (Desloratadine).

Special Populations

Geriatric Subjects: In older subjects (≥65 years old; n=17) following multiple-dose administration of Mondeslor (Desloratadine) Tablets, the mean C_max and AUC values for Mondeslor (Desloratadine) were 20% greater than in younger subjects (<65 years old). The oral total body clearance (CL/F) when normalized for body weight was similar between the two age groups. The mean plasma elimination half-life of Mondeslor (Desloratadine) was 33.7 hr in subjects ≥65 years old. The pharmacokinetics for 3-hydroxydesloratadine appeared unchanged in older versus younger subjects. These age-related differences are unlikely to be clinically relevant and no dosage adjustment is recommended in elderly subjects.

Pediatric Subjects: In subjects 6 to 11 years old, a single dose of 5 mL of Mondeslor (Desloratadine) Oral solution containing 2.5 mg of Mondeslor (Desloratadine), resulted in Mondeslor (Desloratadine) plasma concentrations similar to those achieved in adults administered a single 5 mg Mondeslor (Desloratadine) Tablet. In subjects 2 to 5 years old, a single dose of 2.5 mL of Mondeslor (Desloratadine) Oral solution containing 1.25 mg of Mondeslor (Desloratadine), resulted in Mondeslor (Desloratadine) plasma concentrations similar to those achieved in adults administered a single 5-mg Mondeslor (Desloratadine) Tablet. However, the C_max and AUC of the metabolite (3-hydroxydesloratadine) were 1.27 and 1.61 times higher for the 5 mg dose of Oral solution administered in adults compared to the C_max and AUC obtained in children 2 to 11 years of age receiving 1.25-2.5 mg of Mondeslor (Desloratadine) Oral solution. A single dose of either 2.5 mL or 1.25 mL of Mondeslor (Desloratadine) Oral solution containing 1.25 mg or 0.625 mg, respectively, of Mondeslor (Desloratadine) was administered to subjects 6 to 11 months of age and 12 to 23 months of age. The results of a population pharmacokinetic analysis indicated that a dose of 1 mg for subjects aged 6 to 11 months and 1.25 mg for subjects 12 to 23 months of age is required to obtain Mondeslor (Desloratadine) plasma concentrations similar to those achieved in adults administered a single 5 mg dose of Mondeslor (Desloratadine) Oral solution.

Renally Impaired: Mondeslor (Desloratadine) pharmacokinetics following a single dose of 7.5 mg were characterized in patients with mild (n=7; creatinine clearance 51-69 mL/min/1.73 m²), moderate (n=6; creatinine clearance 34-43 mL/min/1.73 m²), and severe (n=6; creatinine clearance 5-29 mL/min/1.73 m²) renal impairment or hemodialysis dependent (n=6) patients. In patients with mild and moderate renal impairment, median C_max and AUC values increased by approximately 1.2- and 1.9-fold, respectively, relative to subjects with normal renal function. In patients with severe renal impairment or who were hemodialysis dependent, C_max and AUC values increased by approximately 1.7- and 2.5-fold, respectively. Minimal changes in 3-hydroxydesloratadine concentrations were observed. Mondeslor (Desloratadine) and 3-hydroxydesloratadine were poorly removed by hemodialysis. Plasma protein binding of Mondeslor (Desloratadine) and 3-hydroxydesloratadine was unaltered by renal impairment. Dosage adjustment for patients with renal impairment is recommended [see Dosage and Administration (2.5) ].

Hepatically Impaired: Mondeslor (Desloratadine) pharmacokinetics were characterized following a single oral dose in patients with mild (n=4), moderate (n=4), and severe (n=4) hepatic impairment as defined by the Child-Pugh classification of hepatic function and 8 subjects with normal hepatic function. Patients with hepatic impairment, regardless of severity, had approximately a 2.4-fold increase in AUC as compared with normal subjects. The apparent oral clearance of Mondeslor (Desloratadine) in patients with mild, moderate, and severe hepatic impairment was 37%, 36%, and 28% of that in normal subjects, respectively. An increase in the mean elimination half-life of Mondeslor (Desloratadine) in patients with hepatic impairment was observed. For 3-hydroxydesloratadine, the mean C_max and AUC values for patients with hepatic impairment were not statistically significantly different from subjects with normal hepatic function. Dosage adjustment for patients with hepatic impairment is recommended [see Dosage and Administration (2.5) ].

Gender: Female subjects treated for 14 days with Mondeslor (Desloratadine) Tablets had 10% and 3% higher Mondeslor (Desloratadine) C_max and AUC values, respectively, compared with male subjects. The 3-hydroxydesloratadine C_max and AUC values were also increased by 45% and 48%, respectively, in females compared with males. However, these apparent differences are not likely to be clinically relevant and therefore no dosage adjustment is recommended.

Race: Following 14 days of treatment with Mondeslor (Desloratadine) Tablets, the C_max and AUC values for Mondeslor (Desloratadine) were 18% and 32% higher, respectively, in Blacks compared with Caucasians. For 3-hydroxydesloratadine there was a corresponding 10% reduction in C_max and AUC values in Blacks compared to Caucasians. These differences are not likely to be clinically relevant and therefore no dose adjustment is recommended.

Drug Interactions: In two controlled crossover clinical pharmacology studies in healthy male (n=12 in each study) and female (n=12 in each study) volunteers, Mondeslor (Desloratadine) 7.5 mg (1.5 times the daily dose) once daily was coadministered with erythromycin 500 mg every 8 hours or ketoconazole 200 mg every 12 hours for 10 days. In three separate controlled, parallel group clinical pharmacology studies, Mondeslor (Desloratadine) at the clinical dose of 5 mg has been coadministered with azithromycin 500 mg followed by 250 mg once daily for 4 days (n=18) or with fluoxetine 20 mg once daily for 7 days after a 23-day pretreatment period with fluoxetine (n=18) or with cimetidine 600 mg every 12 hours for 14 days (n=18) under steady-state conditions to normal healthy male and female volunteers. Although increased plasma concentrations (C_max and AUC 0-24 hrs) of Mondeslor (Desloratadine) and 3-hydroxydesloratadine were observed, there were no clinically relevant changes in the safety profile of Mondeslor (Desloratadine), as assessed by electrocardiographic parameters (including the corrected QT interval), clinical laboratory tests, vital signs, and adverse events.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity Studies:

The carcinogenic potential of Mondeslor was assessed using a loratadine study in rats and a Mondeslor (Desloratadine) study in mice. In a 2-year study in rats, loratadine was administered in the diet at doses up to 25 mg/kg/day (estimated Mondeslor (Desloratadine) and Mondeslor (Desloratadine) metabolite exposures were approximately 30 times the AUC in humans at the recommended daily oral dose). A significantly higher incidence of hepatocellular tumors (combined adenomas and carcinomas) was observed in males given 10 mg/kg/day of loratadine and in males and females given 25 mg/kg/day of loratadine. The estimated Mondeslor (Desloratadine) and Mondeslor (Desloratadine) metabolite exposures in rats given 10 mg/kg of loratadine were approximately 7 times the AUC in humans at the recommended daily oral dose. The clinical significance of these findings during long-term use of Mondeslor (Desloratadine) is not known.

In a 2-year dietary study in mice, males and females given up to 16 mg/kg/day and 32 mg/kg/day Mondeslor (Desloratadine), respectively, did not show significant increases in the incidence of any tumors. The estimated Mondeslor (Desloratadine) and Mondeslor (Desloratadine) metabolite exposures in mice at these doses were 12 and 27 times, respectively, the AUC in humans at the recommended daily oral dose.

Genotoxicity Studies:

In genotoxicity studies with Mondeslor (Desloratadine), there was no evidence of genotoxic potential in a reverse mutation assay (Salmonella/E. coli mammalian microsome bacterial mutagenicity assay) or in 2 assays for chromosomal aberrations (human peripheral blood lymphocyte clastogenicity assay and mouse bone marrow micronucleus assay).

Impairment of Fertility:

There was no effect on female fertility in rats at Mondeslor (Desloratadine) doses up to 24 mg/kg/day (estimated Mondeslor (Desloratadine) and Mondeslor (Desloratadine) metabolite exposures were approximately 130 times the AUC in humans at the recommended daily oral dose). A male specific decrease in fertility, demonstrated by reduced female conception rates, decreased sperm numbers and motility, and histopathologic testicular changes, occurred at an oral Mondeslor (Desloratadine) dose of 12 mg/kg in rats (estimated Mondeslor (Desloratadine) and Mondeslor (Desloratadine) metabolite exposures were approximately 45 times the AUC in humans at the recommended daily oral dose). Mondeslor (Desloratadine) had no effect on fertility in rats at an oral dose of 3 mg/kg/day (estimated Mondeslor (Desloratadine) and Mondeslor (Desloratadine) metabolite exposures were approximately 8 times the AUC in humans at the recommended daily oral dose).

13.2 Animal Toxicology and/or Pharmacology

Reproductive Toxicology Studies:

Mondeslor (Desloratadine) was not teratogenic in rats at doses up to 48 mg/kg/day (estimated Mondeslor (Desloratadine) and Mondeslor (Desloratadine) metabolite exposures were approximately 210 times the AUC in humans at the recommended daily oral dose) or in rabbits at doses up to 60 mg/kg/day (estimated Mondeslor (Desloratadine) exposures were approximately 230 times the AUC in humans at the recommended daily oral dose). In a separate study, an increase in pre-implantation loss and a decreased number of implantations and fetuses were noted in female rats at 24 mg/kg (estimated Mondeslor (Desloratadine) and Mondeslor (Desloratadine) metabolite exposures were approximately 120 times the AUC in humans at the recommended daily oral dose). Reduced body weight and slow righting reflex were reported in pups at doses of 9 mg/kg/day or greater (estimated Mondeslor (Desloratadine) and Mondeslor (Desloratadine) metabolite exposures were approximately 50 times or greater than the AUC in humans at the recommended daily oral dose). Mondeslor (Desloratadine) had no effect on pup development at an oral dose of 3 mg/kg/day (estimated Mondeslor (Desloratadine) and Mondeslor (Desloratadine) metabolite exposures were approximately 7 times the AUC in humans at the recommended daily oral dose).

14 CLINICAL STUDIES

14.1 Seasonal Allergic Rhinitis

The clinical efficacy and safety of Mondeslor Tablets were evaluated in over 2,300 patients 12 to 75 years of age with seasonal allergic rhinitis. A total of 1,838 patients received 2.5 to 20 mg/day of Mondeslor (Desloratadine) in 4 double-blind, randomized, placebo-controlled clinical trials of 2 to 4 weeks' duration conducted in the United States. The results of these studies demonstrated the efficacy and safety of Mondeslor (Desloratadine) 5 mg in the treatment of adult and adolescent patients with seasonal allergic rhinitis. In a dose-ranging trial, Mondeslor (Desloratadine) 2.5 to 20 mg/day was studied. Doses of 5, 7.5, 10, and 20 mg/day were superior to placebo; and no additional benefit was seen at doses above 5.0 mg. In the same study, an increase in the incidence of somnolence was observed at doses of 10 mg/day and 20 mg/day (5.2% and 7.6%, respectively), compared to placebo (2.3%).

In two 4-week studies of 924 patients (aged 15 to 75 years) with seasonal allergic rhinitis and concomitant asthma, Mondeslor (Desloratadine) Tablets 5 mg once daily improved rhinitis symptoms, with no decrease in pulmonary function. This supports the safety of administering Mondeslor (Desloratadine) Tablets to adult patients with seasonal allergic rhinitis with mild to moderate asthma.

Mondeslor (Desloratadine) Tablets 5 mg once daily significantly reduced the Total Symptom Score (the sum of individual scores of nasal and non-nasal symptoms) in patients with seasonal allergic rhinitis. See Table 3.

There were no significant differences in the effectiveness of Mondeslor (Desloratadine) Tablets 5 mg across subgroups of patients defined by gender, age, or race.

14.2 Perennial Allergic Rhinitis

The clinical efficacy and safety of Mondeslor (Desloratadine) Tablets 5 mg were evaluated in over 1,300 patients 12 to 80 years of age with perennial allergic rhinitis. A total of 685 patients received 5 mg/day of Mondeslor (Desloratadine) in two double-blind, randomized, placebo-controlled clinical trials of 4 weeks' duration conducted in the United States and internationally. In one of these studies Mondeslor (Desloratadine) Tablets 5 mg once daily was shown to significantly reduce the Total Symptom Score in patients with perennial allergic rhinitis (Table 4).

14.3 Chronic Idiopathic Urticaria

The efficacy and safety of Mondeslor (Desloratadine) Tablets 5 mg once daily was studied in 416 chronic idiopathic urticaria patients 12 to 84 years of age, of whom 211 received Mondeslor (Desloratadine). In two double-blind, placebo-controlled, randomized clinical trials of six weeks duration, at the pre-specified one-week primary time point evaluation, Mondeslor (Desloratadine) Tablets significantly reduced the severity of pruritus when compared to placebo (Table 5). Secondary endpoints were also evaluated, and during the first week of therapy Mondeslor (Desloratadine) Tablets 5 mg reduced the secondary endpoints, "Number of Hives" and the "Size of the Largest Hive," when compared to placebo.

16 HOW SUPPLIED/STORAGE AND HANDLING

Mondeslor (Desloratadine) Tablets: Debossed "5", light blue, round tablets that are packaged in high-density polyethylene plastic bottles of 30 (NDC 76439-107-30), 100 (NDC 76439-0107-10) and 500 (NDC 76439-107-50).

Storage:

• Mondeslor (Desloratadine) Tablets: Store at 25° C (77° F); excursions permitted to 15° C - 30° C (59° F - 86° F) Heat sensitive. Avoid exposure at or above 30° C (86° F).
  

  Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.

17 PATIENT COUNSELING INFORMATION

.

17.1 Information for Patients

• Patients should be instructed to use Mondeslor (Desloratadine) Tablets as directed.
• As there are no food effects on bioavailability, patients can be instructed that Mondeslor (Desloratadine) Tablets may be taken without regard to meals.
• Patients should be advised not to increase the dose or dosing frequency as studies have not demonstrated increased effectiveness at higher doses and somnolence may occur.

Manufactured by

Belcher Pharmaceuticals, LLC.

12393 Belcher Road, Suite 420

Largo, FL 33773

Manufactured for:

Virtus Pharmaceuticals

Tampa, FL 33619

www.virtusRX.com

MADE IN USA

Rev. 04/12

PATIENT INFORMATION

Mondeslor (Desloratadine) Tablets, 5 mg

Read the Patient Information that comes with Mondeslor (Desloratadine) tablets before you start taking it and each time you get a refill. There may be new information. This leaflet is a summary of the information for patients. Your doctor or pharmacist can give you additional information. This leaflet does not take the place of talking to your doctor about your medical condition or treatment.

What are Mondeslor (Desloratadine) tablets?

Mondeslor (Desloratadine) tablets are a prescription medicine that contains the medicine Mondeslor (Desloratadine) (an antihistamine).

Mondeslor (Desloratadine) tablets are used to help control the symptoms of:

• seasonal allergic rhinitis (sneezing, stuffy nose, runny nose and itching of the nose) in people 12 years of age and older.
• perennial allergic rhinitis (sneezing, stuffy nose, runny nose and itching of the nose) in people 12 years of age and older.
• Chronic idiopathic urticaria (long term itching) and to reduce the number and size of hives in people 12 years of age and older.

Mondeslor (Desloratadine) Tablets, 5 mg is not for children younger than 12 years of age.

Who should not take Mondeslor (Desloratadine) tablets?

Do not take Mondeslor (Desloratadine) tablets if you:

• are allergic to Mondeslor (Desloratadine) or any of the ingredients in Mondeslor (Desloratadine) Tablets. See the end of this leaflet for a complete list of ingredients.
• are allergic to loratadine (Alavert, Claritin).

Talk to your doctor before taking this medicine if you have any questions about whether or not to take this medicine.

What should I tell my doctor before taking Mondeslor (Desloratadine) tablets?

Before you take Mondeslor (Desloratadine) Tablets, tell your doctor if you:

• have liver or kidney problems.
• have any other medical conditions.
• are pregnant or plan to become pregnant. It is not known if Mondeslor (Desloratadine) will harm your unborn baby. Talk to your doctor if you are pregnant or plan to become pregnant.
• are breast-feeding or plan to breast-feed. Mondeslor (Desloratadine) can pass into your breast milk.

Talk to your doctor about the best way to feed your baby if you take Mondeslor (Desloratadine) tablets.

Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins and herbal supplements. Mondeslor (Desloratadine) may affect the way other medicines work, and other medicines may affect how Mondeslor (Desloratadine) works. Especially tell your doctor if you take:

• ketoconazole (Nizoral)
• erythromycin (Ery-tab, Eryc, PCE)
• azithromycin (Zithromax, Zmax)
• antihistamines
• fluoxetine (Prozac)
• cimetidine (Tagamet)

Know the medicines you take. Keep a list of your medicines and show it to your doctor and pharmacist when you get a new medicine.

How should I take Mondeslor (Desloratadine) Tablets?

• Take Mondeslor (Desloratadine) tablets exactly as your doctor tells you to take it.
• Do not change your dose of Mondeslor (Desloratadine) tablets or take more often than prescribed.
• Mondeslor (Desloratadine) tablets can be taken with or without food.
• If you take too much Mondeslor (Desloratadine) tablets, call your doctor or get medical attention right away.

What are the possible side effects of Mondeslor (Desloratadine) Tablets?

Mondeslor (Desloratadine) tablets may cause serious side effects, including:

Allergic reactions. Stop taking Mondeslor (Desloratadine) tablets and call your doctor right away or get emergency help if you have any of these symptoms:

• rash
• itching
• hives
• swelling of your lips, tongue, face, and throat
• shortness of breath or trouble breathing

The most common side effects of Mondeslor (Desloratadine) tablets in adults and children 12 years of age and older with allergic rhinitis include:

• sore throat
• dry mouth
• muscle pain
• tiredness
• sleepiness
• menstrual pain

Increased sleepiness or tiredness can happen if you take more Mondeslor (Desloratadine) Tablets than your doctor prescribed to you.

Tell your doctor if you have any side effect that bothers you or that does not go away.

These are not all of the possible side effects of Mondeslor (Desloratadine) Tablets. For more information, ask your doctor or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to Virtus Pharmaceuticals at 813-283-1344 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

How should I store Mondeslor (Desloratadine) Tablets?

• Store Mondeslor (Desloratadine) Tablets between 59°F to 86°F (15°C to 30°C).
• Mondeslor (Desloratadine) Tablets are sensitive to heat. Do not store above 86°F (30°C).
• Protect Mondeslor (Desloratadine) Tablets from moisture.

Keep Mondeslor (Desloratadine) Tablets, and all medicines out of the reach of children.

General information about Mondeslor (Desloratadine) Tablets

Medicines are sometimes prescribed for purposes other than those listed in a patient information leaflet. Do not use Mondeslor (Desloratadine) Tablets for a condition for which it was not prescribed. Do not give Mondeslor (Desloratadine) Tablets to other people, even if they have the same condition you have. It may harm them.

This Patient Information leaflet summarizes the most important information about Mondeslor (Desloratadine) tablets. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about Mondeslor (Desloratadine) Tablets that is written for health professionals.

What are the ingredients in Mondeslor (Desloratadine) Tablets?

Active ingredient: Mondeslor (Desloratadine)

Inactive ingredients in Mondeslor (Desloratadine) Tablets: microcrystalline cellulose NF, pregelatinized starch NF, croscarmellose sodium NF, talc USP, zinc stearate, USP and FD&C Blue #2 HT 11-14%.

Manufactured by

Belcher Pharmaceuticals, LLC.

12393 Belcher Road, Suite 420

Largo, FL 33773

Manufactured for:

Virtus Pharmaceuticals

Tampa, FL 33619

www.virtusRX.com

MADE IN USA

April 2012

L05I-VIR

R-1204

Mondeslor (Desloratadine) 5mg tablet

Chemical Structure

Montelukast:

• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Drug interactions
• Use in specific populations
• Overdosage
• Description
• Clinical pharmacology
• Nonclinical toxicology
• Clinical studies
• How supplied/storage and handling
• Patient counseling information
• Patient information
• Mondeslor (Montelukast) reviews

1 INDICATIONS AND USAGE

Mondeslor sodium tablets are a leukotriene receptor antagonist indicated for:

• Prophylaxis and chronic treatment of asthma in patients 2 years of age and older (1.1).
• Acute prevention of exercise-induced bronchoconstriction (EIB) in patients 15 years of age and older (1.2)
• Relief of symptoms of allergic rhinitis (AR): seasonal allergic rhinitis (SAR) in patients 2 years of age and older, and perennial allergic rhinitis (PAR) in patients 2 years of age and older (1.3).

1.1 Asthma

Mondeslor (Montelukast) sodium is indicated for the prophylaxis and chronic treatment of asthma in adults and pediatric patients 2 years of age and older.

1.2 Exercise-Induced Bronchoconstriction

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

Pediatric use information for patients ages 6 to 14 years of age for acute prevention of exercise-induced bronchoconstriction (EIB) is approved for Merck Sharp & Dohme Corp’s Mondeslor (Montelukast) tablet products. However, due to Merck Sharp & Dohme Corp’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

1.3 Allergic Rhinitis

Mondeslor (Montelukast) sodium is indicated for the relief of symptoms of seasonal allergic rhinitis in patients 2 years of age and older and perennial allergic rhinitis in patients 2 years of age and older.

2 DOSAGE AND ADMINISTRATION

Administration :

• Asthma ( 2.1 ): Once daily in the evening for patients 2 years and older.
• Acute prevention of EIB ( 2.2 ): 10 mg tablet at least 2 hours before exercise for patients 15 years of age and older.
• Seasonal allergic rhinitis ( 2.3 ): Once daily for patients 2 years and older.
• Perennial allergic rhinitis ( 2.3 ): Once daily for patients 2 years of age and older.

Dosage (by age)

• 15 years and older: one 10 mg tablet
• 6 to 14 years: one 5 mg chewable tablet
• 2 to 5 years: one 4 mg chewable tablet

Patients with both asthma and allergic rhinitis should take only one dose daily in the evening ( 2.4 ).

2.1 Asthma

Mondeslor (Montelukast) sodium should be taken once daily in the evening. The following doses are recommended:

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

For pediatric patients 6 to 14 years of age: one 5 mg chewable tablet.

For pediatric patients 2 to 5 years of age: one 4 mg chewable tablet

Safety and effectiveness in pediatric patients less than 12 months of age with asthma have not been established.

There have been no clinical trials in patients with asthma to evaluate the relative efficacy of morning versus evening dosing. The pharmacokinetics of Mondeslor (Montelukast) are similar whether dosed in the morning or evening. Efficacy has been demonstrated for asthma when Mondeslor (Montelukast) was administered in the evening without regard to time of food ingestion.

2.2 Exercise-Induced Bronchoconstriction in Patients 15 Years of Age and Older

For prevention of EIB, a single 10 mg dose of Mondeslor (Montelukast) should be taken at least 2 hours before exercise.

An additional dose of Mondeslor (Montelukast) should not be taken within 24 hours of a previous dose. Patients already taking Mondeslor (Montelukast) sodium 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. Safety and effectiveness in patients younger than 15 years of age have not been established. Daily administration of Mondeslor (Montelukast) sodium for the chronic treatment of asthma has not been established to prevent acute episodes of EIB.

Pediatric use information for patients ages 6 to 14 years of age for acute prevention of exercise-induced bronchoconstriction (EIB) is approved for Merck Sharp & Dohme Corp’s Mondeslor (Montelukast) tablet products. However, due to Merck Sharp & Dohme Corp’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

2.3 Allergic Rhinitis

For allergic rhinitis, Mondeslor sodium should be taken once daily. Efficacy was demonstrated for seasonal allergic rhinitis when Mondeslor (Montelukast) was administered in the morning or the evening without regard to time of food ingestion. The time of administration may 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.

For pediatric patients 6 to 14 years of age: one 5 mg chewable tablet.

For pediatric patients 2 to 5 years of age: one 4 mg chewable tablet

Safety and effectiveness in pediatric patients younger than 2 years of age with seasonal allergic rhinitis have not been established.

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.

For pediatric patients 6 to 14 years of age: one 5 mg chewable tablet.

For pediatric patients 2 to 5 years of age: one 4 mg chewable tablet

Safety and effectiveness in pediatric patients younger than 6 months of age with perennial allergic rhinitis have not been established.

2.4 Asthma and Allergic Rhinitis

Patients with both asthma and allergic rhinitis should take only one Mondeslor (Montelukast) sodium dose daily in the evening.

3 DOSAGE FORMS AND STRENGTHS

• Mondeslor (Montelukast) sodium tablets, 10 mg (montelukast) are beige colored, round, biconvex, film coated tablets with "SZ 344" debossed on one side and plain on other side.
• Mondeslor (Montelukast) sodium chewable tablets, 4 mg (montelukast) are pink colored, round, mottled and debossed “SZ 74” on one side and plain on the other side.
• Mondeslor (Montelukast) sodium chewable tablets, 5 mg (montelukast) are pink colored, round, mottled and debossed “SZ 76” on one side and plain on other side.

• Mondeslor (Montelukast) sodium film-coated tablets, 10 mg ( Mondeslor (Montelukast))
• Mondeslor (Montelukast) sodium chewable tablets, 4 mg and 5 mg (montelukast)

4 CONTRAINDICATIONS

Hypersensitivity to any component of this product.

• Hypersensitivity to any component of this product ( 4 ).

5 WARNINGS AND PRECAUTIONS

• Do not prescribe Mondeslor sodium to treat an acute asthma attack ( 5.1 ).
• Advise patients to have appropriate rescue medication available ( 5.1 ).
• Inhaled corticosteroid may be reduced gradually. Do not abruptly substitute Mondeslor (Montelukast) sodium for inhaled or oral corticosteroids ( 5.2 ).
• Patients with known aspirin sensitivity should continue to avoid aspirin or non-steroidal anti-inflammatory agents while taking Mondeslor (Montelukast) sodium ( 5.3 ).
• Neuropsychiatric events have been reported with Mondeslor (Montelukast) sodium. Instruct patients to be alert for neuropsychiatric events. Evaluate the risks and benefits of continuing treatment with Mondeslor (Montelukast) sodium if such events occur ( 5.4 and 6.2 ).
• Systemic eosinophilia, sometimes presenting with clinical features of vasculitis consistent with Churg-Strauss syndrome, has been reported. These events usually, but not always, have been associated with the reduction of oral corticosteroid therapy ( 5.5 and 6.2 ).
• Inform patients with phenylketonuria that the 4 mg and 5 mg chewable tablets contain phenylalanine ( 5.6 ).

5.1 Acute Asthma

Mondeslor (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 Mondeslor (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.

5.2 Concomitant Corticosteroid Use

While the dose of inhaled corticosteroid may be reduced gradually under medical supervision, Mondeslor sodium should not be abruptly substituted for inhaled or oral corticosteroids.

5.3 Aspirin Sensitivity

Patients with known aspirin sensitivity should continue avoidance of aspirin or non-steroidal anti-inflammatory agents while taking Mondeslor (Montelukast) sodium. Although Mondeslor (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 aspirin-sensitive asthmatic patients [see CLINICAL STUDIES (14.1)].

5.4 Neuropsychiatric Events

Neuropsychiatric events have been reported in adult, adolescent, and pediatric patients taking Mondeslor sodium. Post-marketing reports with Mondeslor (Montelukast) sodium use include agitation, aggressive behavior or hostility, anxiousness, depression, disorientation, dream abnormalities, hallucinations, insomnia, irritability, restlessness, somnambulism, suicidal thinking and behavior (including suicide), and tremor. The clinical details of some post-marketing reports involving Mondeslor (Montelukast) sodium appear consistent with a drug-induced effect.

Patients and prescribers should be alert for neuropsychiatric events. Patients should be instructed to notify their prescriber if these changes occur. Prescribers should carefully evaluate the risks and benefits of continuing treatment with Mondeslor (Montelukast) sodium if such events occur [see ADVERSE REACTIONS (6.2)].

5.5 Eosinophilic Conditions

Patients with asthma on therapy with Mondeslor (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 usually, but not always, have been 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 Mondeslor (Montelukast) sodium and these underlying conditions has not been established [see ADVERSE REACTIONS (6.2)].

5.6 Phenylketonuria

Phenylketonuric patients should be informed that the 4 mg and 5 mg chewable tablets contain phenylalanine (a component of aspartame), 0.48 mg and 0.60 mg per 4 mg and 5 mg chewable tablet, respectively.

6 ADVERSE REACTIONS

Most common adverse reactions : upper respiratory infection, fever, headache, pharyngitis, cough, abdominal pain, diarrhea, otitis media, influenza, rhinorrhea, sinusitis, otitis ( 6.1 ).

To report SUSPECTED ADVERSE REACTIONS, contact Sandoz Inc., at 1-800-525-8747 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

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

Mondeslor (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 experiences reported with Mondeslor (Montelukast) sodium occurred in greater than or equal to 1% of patients and at an incidence greater than that in patients treated with placebo:

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

The frequency of less common adverse events was comparable between Mondeslor (Montelukast) sodium and placebo.

The safety profile of Mondeslor (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 Mondeslor (Montelukast) sodium.

Cumulatively, 569 patients were treated with Mondeslor (Montelukast) sodium 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

Mondeslor (Montelukast) sodium has been evaluated for safety in 476 pediatric patients 6 to 14 years of age. Cumulatively, 289 pediatric patients were treated with Mondeslor (Montelukast) sodium for at least 6 months, and 241 for one year or longer in clinical trials. The safety profile of Mondeslor (Montelukast) sodium 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 Mondeslor (Montelukast) sodium, 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 Mondeslor (Montelukast) sodium and placebo. With prolonged treatment, the adverse experience profile did not significantly change.

Pediatric use information for patients ages 6 to 14 years of age for acute prevention of exercise-induced bronchoconstriction (EIB) is approved for Merck Sharp & Dohme Corp’s Mondeslor (Montelukast) tablet products. However, due to Merck Sharp & Dohme Corp’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

In studies evaluating growth rate, the safety profile in these pediatric patients was consistent with the safety profile previously described for Mondeslor (Montelukast) sodium. In a 56-week, double-blind study evaluating growth rate in pediatric patients 6 to 8 years of age receiving Mondeslor (Montelukast) sodium, the following events not previously observed with the use of Mondeslor (Montelukast) sodium 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

Mondeslor (Montelukast) sodium 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 Mondeslor (Montelukast) sodium 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 Mondeslor (Montelukast) sodium, 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.

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

Mondeslor (Montelukast) sodium has been evaluated for safety in 2199 adult and adolescent patients 15 years of age and older in clinical trials. Mondeslor (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 event was reported with Mondeslor (Montelukast) sodium with a frequency ≥1% and at an incidence greater than placebo: upper respiratory infection, 1.9% of patients receiving Mondeslor (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.

Pediatric Patients 2 to 14 Years of Age with Seasonal Allergic Rhinitis

Mondeslor (Montelukast) sodium 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. Mondeslor (Montelukast) sodium 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

Mondeslor (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 Mondeslor (Montelukast) sodium in two, 6-week, clinical studies. Mondeslor (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 events were reported with Mondeslor (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.

Pediatric Patients 2 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.

6.2 Post-Marketing Experience

The following adverse reactions have been identified during post-approval use of Mondeslor (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: agitation including aggressive behavior or hostility, anxiousness, depression, disorientation, dream abnormalities, hallucinations, insomnia, irritability, restlessness, somnambulism, suicidal thinking and behavior (including suicide), tremor [see WARNINGS AND PRECAUTIONS (5.4)].

Nervous system disorders: drowsiness, paraesthesia/hypoesthesia, seizures.

Cardiac disorders: palpitations.

Respiratory, thoracic and mediastinal disorders: epistaxis.

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 Mondeslor (Montelukast) sodium. Most of these occurred in combination with other confounding factors, such as use of other medications, or when Mondeslor (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, urticaria.

Musculoskeletal and connective tissue disorders: arthralgia, myalgia including muscle cramps.

General disorders and administration site conditions: edema.

Patients with asthma on therapy with Mondeslor (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 usually, but not always, have been 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)].

7 DRUG INTERACTIONS

No dose adjustment is needed when Mondeslor (Montelukast) sodium is co-administered with theophylline, prednisone, prednisolone, oral contraceptives, terfenadine, digoxin, warfarin, thyroid hormones, sedative hypnotics, non-steroidal anti-inflammatory agents, benzodiazepines, decongestants, and Cytochrome P450 (CYP) enzyme inducers [see CLINICAL PHARMACOLOGY (12.3)].

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category B: There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, Mondeslor sodium should be used during pregnancy only if clearly needed.

Teratogenic Effect: No teratogenicity was observed in rats and rabbits at doses approximately 100 and 110 times, respectively, the maximum recommended daily oral dose in adults based on AUCs [see NONCLINICAL TOXICOLOGY (13.2)].

During worldwide marketing experience, congenital limb defects have been rarely reported in the offspring of women being treated with Mondeslor (Montelukast) sodium during pregnancy. Most of these women were also taking other asthma medications during their pregnancy. A causal relationship between these events and Mondeslor (Montelukast) sodium has not been established.

8.3 Nursing Mothers

Studies in rats have shown that Mondeslor (Montelukast) is excreted in milk. It is not known if Mondeslor (Montelukast) is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Mondeslor (Montelukast) sodium is given to a nursing mother.

8.4 Pediatric Use

Safety and efficacy of Mondeslor sodium have been established in adequate and well-controlled studies in pediatric patients with asthma 6 to 14 years of age. Safety and efficacy profiles in this age group are similar to those seen in adults [see ADVERSE REACTIONS (6.1), CLINICAL PHARMACOLOGY, Special Populations (12.3), AND CLINICAL STUDIES (14.1, 14.2)].

The efficacy of Mondeslor (Montelukast) sodium for the treatment of seasonal allergic rhinitis in pediatric patients 2 to 14 years of age and for the treatment of perennial allergic rhinitis in pediatric patients 2 to 14 years of age is supported by extrapolation from the demonstrated efficacy in patients 15 years of age and older with allergic rhinitis as well as the assumption that the disease course, pathophysiology and the drug’s effect are substantially similar among these populations.

The safety of Mondeslor (Montelukast) sodium chewable tablets, 4 mg in pediatric patients 2 to 5 years of age with asthma has been demonstrated by adequate and well-controlled data [see ADVERSE REACTIONS (6.1)]. Efficacy of Mondeslor (Montelukast) sodium in this age group is extrapolated from the demonstrated efficacy in patients 6 years of age and older with asthma and is based on similar pharmacokinetic data, as well as the assumption that the disease course, pathophysiology and the drug’s effect are substantially similar among these populations. Efficacy in this age group is supported by exploratory efficacy assessments from a large, well-controlled safety study conducted in patients 2 to 5 years of age.

The safety of Mondeslor (Montelukast) sodium chewable tablets, 4 mg and 5 mg in pediatric patients aged 2 to 14 years with allergic rhinitis is supported by data from studies conducted in pediatric patients aged 2 to 14 years with asthma. A safety study in pediatric patients 2 to 14 years of age with seasonal allergic rhinitis demonstrated a similar safety profile [see ADVERSE REACTIONS (6.1)].

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

Pediatric use information for patients ages 6 to 14 years of age for acute prevention of exercise-induced bronchoconstriction (EIB) is approved for Merck Sharp & Dohme Corp’s Mondeslor (Montelukast) tablet products. However, due to Merck Sharp & Dohme Corp’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

Growth Rate in Pediatric Patients

A 56-week, multi-center, double-blind, randomized, active- and placebo-controlled parallel group study was conducted to assess the effect of Mondeslor (Montelukast) sodium on growth rate in 360 patients with mild asthma, aged 6 to 8 years. Treatment groups included Mondeslor (Montelukast) 5 mg once daily, placebo, and beclomethasone dipropionate administered as 168 mcg twice daily with a spacer device. For each subject, a growth rate was defined as the slope of a linear regression line fit to the height measurements over 56 weeks. The primary comparison was the difference in growth rates between Mondeslor (Montelukast) sodium and placebo groups. Growth rates, expressed as least-squares (LS) mean (95% CI) in cm/year, for the Mondeslor (Montelukast) sodium, placebo, and beclomethasone treatment groups were 5.67 (5.46, 5.88), 5.64 (5.42, 5.86), and 4.86 (4.64, 5.08), respectively. The differences in growth rates, expressed as least-squares (LS) mean (95% CI) in cm/year, for Mondeslor (Montelukast) sodium minus placebo, beclomethasone minus placebo, and Mondeslor (Montelukast) sodium minus beclomethasone treatment groups were 0.03 (-0.26, 0.31), -0.78 (-1.06, -0.49); and 0.81 (0.53, 1.09), respectively. Growth rate (expressed as mean change in height over time) for each treatment group is shown in FIGURE 1.

FIGURE 1: Change in Height (cm) from Randomization Visit by Scheduled Week (Treatment Group Mean ± Standard Error* of the Mean)

^*The standard errors of the treatment group means in change in height are too small to be visible on the plot

8.5 Geriatric Use

Of the total number of subjects in clinical studies of Mondeslor (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 Mondeslor (Montelukast) are similar in elderly and younger adults. The plasma half-life of Mondeslor (Montelukast) is slightly longer in the elderly. No dosage adjustment in the elderly is required.

8.6 Hepatic Insufficiency

No dosage adjustment is required in patients with mild-to-moderate hepatic insufficiency [see CLINICAL PHARMACOLOGY ].

8.7 Renal Insufficiency

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

10 OVERDOSAGE

No mortality occurred following single oral doses of Mondeslor (Montelukast) up to 5000 mg/kg in mice (estimated exposure was approximately 335 and 210 times the AUC for adults and children, respectively, at the maximum recommended daily oral dose) and rats (estimated exposure was approximately 230 and 145 times the AUC for adults and children, respectively, at the maximum recommended daily oral dose).

No specific information is available on the treatment of overdosage with Mondeslor (Montelukast) sodium. In chronic asthma studies, Mondeslor (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 a week without clinically important adverse experiences. 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.

There have been reports of acute overdosage in post-marketing experience and clinical studies with Mondeslor (Montelukast) sodium. These include reports in adults and children with a dose as high as 1000 mg. The clinical and laboratory findings observed were consistent with the safety profile in adults and pediatric patients. There were no adverse experiences in the majority of overdosage reports. The most frequently occurring adverse experiences were consistent with the safety profile of Mondeslor (Montelukast) sodium and included abdominal pain, somnolence, thirst, headache, vomiting and psychomotor hyperactivity.

It is not known whether Mondeslor (Montelukast) is removed by peritoneal dialysis or hemodialysis.

11 DESCRIPTION

Mondeslor (Montelukast) sodium, the active ingredient in Mondeslor (Montelukast) sodium tablets, is a selective and orally active leukotriene receptor antagonist that inhibits the cysteinyl leukotriene CysLT₁ receptor.

Mondeslor (Montelukast) sodium is described chemically as [R-(E)]-1-[[[1-[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl]thio]methyl] cyclopropaneacetic acid, monosodium salt.

The molecular formula is C₃₅H₃₅ClNNaO₃S, and its molecular weight is 608.18. The structural formula is:

Mondeslor (Montelukast) sodium is a hygroscopic, optically active, white to off-white to light yellow powder. Mondeslor (Montelukast) sodium is freely soluble in ethanol, methanol, and water and practically insoluble in acetonitrile.

Each 10 mg film-coated Mondeslor (Montelukast) sodium tablet contains 10.4 mg Mondeslor (Montelukast) sodium, which is equivalent to 10 mg of Mondeslor (Montelukast). In addition Mondeslor (Montelukast) tablets contain the following inactive ingredients: croscarmellose sodium, hydroxypropyl cellulose, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, red ferric oxide, titanium dioxide, and yellow ferric oxide.

Each 4 mg and 5 mg chewable Mondeslor (Montelukast) sodium tablet contains 4.2 and 5.2 mg Mondeslor (Montelukast) sodium, which are equivalent to 4 and 5 mg of Mondeslor (Montelukast), respectively. Mondeslor (Montelukast) chewable tablets contain the following inactive ingredients: artificial cherry durarome flavor, aspartame, cherry flavor, croscarmellose sodium, hydroxypropyl cellulose, magnesium stearate, mannitol, microcrystalline cellulose, and red ferric oxide.

The artificial cherry durarome flavor contain: artificial flavors, maltodextrin, red # 40, silicon dioxide, soy lecithin and sugar.

The cherry flavor contain: artificial flavors, benzyl alcohol, lactic acid, and maltodextrin.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

The cysteinyl leukotrienes 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 (CysLT₁) receptor is found in the human airway (including airway smooth muscle cells and airway macrophages) and on other pro-inflammatory 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.

Mondeslor (Montelukast) is an orally active compound that binds with high affinity and selectivity to the CysLT₁ receptor (in preference to other pharmacologically important airway receptors, such as the prostanoid, cholinergic, or β-adrenergic receptor). Mondeslor (Montelukast) inhibits physiologic actions of LTD₄ at the CysLT₁ receptor without any agonist activity.

12.2 Pharmacodynamics

Mondeslor (Montelukast) causes inhibition of airway cysteinyl leukotriene receptors as demonstrated by the ability to inhibit bronchoconstriction due to inhaled LTD₄ in asthmatics. Doses as low as 5 mg cause substantial blockage of LTD₄-induced bronchoconstriction. In a placebo-controlled, crossover study (n=12), Mondeslor (Montelukast) sodium inhibited early- and late-phase bronchoconstriction due to antigen challenge by 75% and 57%, respectively.

The effect of Mondeslor (Montelukast) sodium on eosinophils in the peripheral blood was examined in clinical trials. In patients with asthma aged 2 years and older who received Mondeslor (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 Mondeslor (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 Mondeslor (Montelukast) sodium. The relationship between these observations and the clinical benefits of Mondeslor (Montelukast) noted in the clinical trials is not known [see CLINICAL STUDIES (14)].

12.3 Pharmacokinetics

Absorption

Mondeslor (Montelukast) is rapidly absorbed following oral administration. After administration of the 10 mg film-coated tablet to fasted adults, the mean peak Mondeslor (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.

For the 5 mg chewable tablet, the mean C_max is achieved in 2 to 2.5 hours after administration to adults in the fasted state. The mean oral bioavailability is 73% in the fasted state versus 63% when administered with a standard meal in the morning.

For the 4 mg chewable tablet, the mean C_max is achieved 2 hours after administration in pediatric patients 2 to 5 years of age in the fasted state.

The 4 mg oral granule formulation is bioequivalent to the 4 mg chewable tablet when administered to adults in the fasted state.

The safety and efficacy of Mondeslor (Montelukast) sodium in patients with asthma were demonstrated in clinical trials in which the 10 mg film-coated tablet and 5 mg chewable tablet formulations were administered in the evening without regard to the time of food ingestion. The safety of Mondeslor (Montelukast) sodium in patients with asthma was also demonstrated in clinical trials in which the 4 mg chewable tablet and 4 mg oral granule formulations were administered in the evening without regard to the time of food ingestion. The safety and efficacy of Mondeslor (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 Mondeslor (Montelukast) when administered as two 5 mg chewable tablets versus one 10 mg film-coated tablet have not been evaluated.

Distribution

Mondeslor (Montelukast) is more than 99% bound to plasma proteins. The steady state volume of distribution of Mondeslor (Montelukast) averages 8 to 11 liters. Studies in rats with radiolabeled Mondeslor (Montelukast) indicate minimal distribution across the blood-brain barrier. In addition, concentrations of radiolabeled material at 24 hours postdose were minimal in all other tissues.

Metabolism

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

In vitro studies using human liver microsomes indicate that CYP3A4 and 2C9 are involved in the metabolism of Mondeslor (Montelukast). Clinical studies investigating the effect of known inhibitors of CYP3A4 (e.g., ketoconazole, erythromycin) or 2C9 (e.g., fluconazole) on Mondeslor (Montelukast) pharmacokinetics have not been conducted. Based on further in vitro results in human liver microsomes, therapeutic plasma concentrations of Mondeslor (Montelukast) do not inhibit CYP3A4, 2C9, 1A2, 2A6, 2C19, or 2D6 [see DRUG INTERACTIONS (7) AND CLINICAL PHARMACOLOGY, Drug-Drug Interactions (12.3)]. In vitro studies have shown that Mondeslor (Montelukast) is a potent inhibitor of CYP2C8; however, data from a clinical drug-drug interaction study involving Mondeslor (Montelukast) and rosiglitazone (a probe substrate representative of drugs primarily metabolized by CYP2C8) demonstrated that Mondeslor (Montelukast) does not inhibit CYP2C8 in vivo, and therefore is not anticipated to alter the metabolism of drugs metabolized by this enzyme [see DRUG INTERACTIONS (7) AND CLINICAL PHARMACOLOGY, Drug-Drug Interactions (12.3)].

Elimination

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

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

Special Populations

Hepatic Insufficiency: Patients with mild-to-moderate hepatic insufficiency and clinical evidence of cirrhosis had evidence of decreased metabolism of Mondeslor (Montelukast) resulting in 41% (90% CI=7%, 85%) higher mean Mondeslor (Montelukast) AUC following a single 10 mg dose. The elimination of Mondeslor (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 Mondeslor (Montelukast) sodium in patients with more severe hepatic impairment or with hepatitis have not been evaluated.

Renal Insufficiency: Since Mondeslor (Montelukast) and its metabolites are not excreted in the urine, the pharmacokinetics of Mondeslor (Montelukast) were not evaluated in patients with renal insufficiency. No dosage adjustment is recommended in these patients.

Gender: The pharmacokinetics of Mondeslor (Montelukast) are similar in males and females.

Race: Pharmacokinetic differences due to race have not been studied.

Adolescents and Pediatric Patients: Pharmacokinetic studies evaluated the systemic exposure of the 4 mg chewable tablets in pediatric patients 2 to 5 years of age, the 5 mg chewable tablets in pediatric patients 6 to 14 years of age, and the 10 mg film-coated tablets in young adults and adolescents ≥15 years of age.

The plasma concentration profile of Mondeslor (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.

The mean systemic exposure of the 4 mg chewable tablet in pediatric patients 2 to 5 years of age and the 5 mg chewable tablets in pediatric patients 6 to 14 years of age is similar to the mean systemic exposure of the 10 mg film-coated tablet in adults. The 5-mg chewable tablet should be used in pediatric patients 6 to 14 years of age and the 4 mg chewable tablet should be used in pediatric patients 2 to 5 years of age.

In children 6 to 11 months of age, the systemic exposure to Mondeslor (Montelukast) and the variability of plasma Mondeslor (Montelukast) concentrations were higher than those observed in adults. Based on population analyses, the mean AUC (4296 ng-hr/mL [range 1200 to 7153]) was 60% higher and the mean C_max (667 ng/mL [range 201 to 1058]) was 89% higher than those observed in adults (mean AUC 2689 ng-hr/mL [range 1521 to 4595]) and mean C_max (353 ng/mL [range 180 to 548]). The systemic exposure in children 12 to 23 months of age was less variable, but was still higher than that observed in adults. The mean AUC (3574 ng-hr/mL [range 2229 to 5408]) was 33% higher and the mean C_max (562 ng/mL [range 296 to 814]) was 60% higher than those observed in adults. Safety and tolerability of Mondeslor (Montelukast) in a single-dose pharmacokinetic study in 26 children 6 to 23 months of age were similar to that of patients two years and above [see ADVERSE REACTIONS (6.1)]. The 4 mg oral granule formulation should be used for pediatric patients 12 to 23 months of age for the treatment of asthma, or for pediatric patients 6 to 23 months of age for the treatment of perennial allergic rhinitis. Since the 4 mg oral granule formulation is bioequivalent to the 4 mg chewable tablet, it can also be used as an alternative formulation to the 4 mg chewable tablet in pediatric patients 2 to 5 years of age.

Drug-Drug Interactions

Theophylline, Prednisone, and Prednisolone: Mondeslor (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 Mondeslor (Montelukast) did not have clinically important effects on the pharmacokinetics of the following drugs: theophylline, prednisone, and prednisolone.

Mondeslor (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]. Mondeslor (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, Terfenadine , Digoxin, and Warfarin: In drug interaction studies, the recommended clinical dose of Mondeslor (Montelukast) did not have clinically important effects on the pharmacokinetics of the following drugs: oral contraceptives (norethindrone 1 mg/ethinyl estradiol 35 mcg), terfenadine, digoxin, and warfarin. Mondeslor (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. Mondeslor (Montelukast) at a dose of 10 mg once daily dosed to pharmacokinetic steady state did not change the plasma concentration profile of terfenadine (a substrate of CYP3A4) or fexofenadine, the carboxylated metabolite, and did not prolong the QTc interval following co-administration with terfenadine 60 mg twice daily; 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, Mondeslor (Montelukast) 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 Mondeslor (Montelukast) approximately 40% following a single 10 mg dose of Mondeslor (Montelukast). No dosage adjustment for Mondeslor (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 Mondeslor (Montelukast) sodium.

Mondeslor (Montelukast) is a potent inhibitor of CYP2C8 in vitro. However, data from a clinical drug-drug interaction study involving Mondeslor (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 Mondeslor (Montelukast) does not inhibit CYP2C8 in vivo. Therefore, Mondeslor (Montelukast) is not anticipated to alter the metabolism of drugs metabolized by this enzyme (e.g., paclitaxel, rosiglitazone, and repaglinide).

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No evidence of tumorigenicity was seen in carcinogenicity studies of either 2 years in Sprague-Dawley rats or 92 weeks in mice at oral gavage doses up to 200 mg/kg/day or 100 mg/kg/day, respectively. The estimated exposure in rats was approximately 120 and 75 times the AUC for adults and children, respectively, at the maximum recommended daily oral dose. The estimated exposure in mice was approximately 45 and 25 times the AUC for adults and children, respectively, at the maximum recommended daily oral dose.

Mondeslor demonstrated no evidence of mutagenic or clastogenic activity in the following assays: the microbial mutagenesis assay, the V-79 mammalian cell mutagenesis assay, the alkaline elution assay in rat hepatocytes, the chromosomal aberration assay in Chinese hamster ovary cells, and in the in vivo mouse bone marrow chromosomal aberration assay.

In fertility studies in female rats, Mondeslor (Montelukast) produced reductions in fertility and fecundity indices at an oral dose of 200 mg/kg (estimated exposure was approximately 70 times the AUC for adults at the maximum recommended daily oral dose). No effects on female fertility or fecundity were observed at an oral dose of 100 mg/kg (estimated exposure was approximately 20 times the AUC for adults at the maximum recommended daily oral dose). Mondeslor (Montelukast) had no effects on fertility in male rats at oral doses up to 800 mg/kg (estimated exposure was approximately 160 times the AUC for adults at the maximum recommended daily oral dose).

13.2 Animal Toxicology and/or Pharmacology

Reproductive Toxicology Studies

No teratogenicity was observed at oral doses up to 400 mg/kg/day and 300 mg/kg/day in rats and rabbits, respectively. These doses were approximately 100 and 110 times the maximum recommended daily oral dose in adults, respectively, based on AUCs. Mondeslor (Montelukast) crosses the placenta following oral dosing in rats and rabbits [see USE IN SPECIFIC POPULATIONS (8.1)].

14 CLINICAL STUDIES

14.1 Asthma

Adults and Adolescents 15 Years of Age and Older with Asthma

Clinical trials in adults and adolescents 15 years of age and older demonstrated there is no additional clinical benefit to Mondeslor doses above 10 mg once daily.

The efficacy of Mondeslor (Montelukast) sodium for the chronic treatment of asthma in adults and adolescents 15 years of age and older was demonstrated in two (U.S. and Multinational) similarly designed, randomized, 12-week, double-blind, placebo-controlled trials in 1576 patients (795 treated with Mondeslor (Montelukast), sodium 530 treated with placebo, and 251 treated with active control). The median age was 33 years (range 15 to 85); 56.8% were females and 43.2% were males. The ethnic/racial distribution in these studies was 71.6% Caucasian, 17.7% Hispanic, 7.2% other origins and 3.5% Black. Patients had mild or moderate asthma and were non-smokers who required approximately 5 puffs of inhaled β-agonist per day on an “as-needed” basis. The patients had a mean baseline percent of predicted forced expiratory volume in 1 second (FEV₁) of 66% (approximate range, 40 to 90%). The co-primary endpoints in these trials were FEV₁ and daytime asthma symptoms. In both studies after 12 weeks, a random subset of patients receiving Mondeslor (Montelukast) sodium was switched to placebo for an additional 3 weeks of double-blind treatment to evaluate for possible rebound effects.

The results of the U.S. trial on the primary endpoint, morning FEV₁, expressed as mean percent change from baseline averaged over the 12-week treatment period, are shown in FIGURE 2. Compared with placebo, treatment with one Mondeslor (Montelukast) sodium 10 mg tablet daily in the evening resulted in a statistically significant increase in FEV₁ percent change from baseline (13%-change in the group treated with Mondeslor (Montelukast) sodium vs. 4.2%-change in the placebo group, p<0.001); the change from baseline in FEV₁ for Mondeslor (Montelukast) sodium was 0.32 liters compared with 0.10 liters for placebo, corresponding to a between-group difference of 0.22 liters (p<0.001, 95% CI 0.17 liters, 0.27 liters). The results of the Multinational trial on FEV₁ were similar.

FIGURE 2: FEV₁ Mean Percent Change from Baseline (U.S. Trial: Mondeslor (Montelukast) Sodium N=406; Placebo N=270) (ANOVA Model)

The effect of Mondeslor (Montelukast) sodium on other primary and secondary endpoints, represented by the Multinational study is shown in TABLE 2. Results on these endpoints were similar in the US study.

*p<0.001, compared with placebo

Both studies evaluated the effect of Mondeslor (Montelukast) sodium on secondary outcomes, including asthma attack (utilization of health-care resources such as an unscheduled visit to a doctor's office, emergency room, or hospital; or treatment with oral, intravenous, or intramuscular corticosteroid), and use of oral corticosteroids for asthma rescue. In the Multinational study, significantly fewer patients (15.6% of patients) on Mondeslor (Montelukast) sodium experienced asthma attacks compared with patients on placebo (27.3%, p< 0.001). In the US study, 7.8% of patients on Mondeslor (Montelukast) sodium and 10.3% of patients on placebo experienced asthma attacks, but the difference between the two treatment groups was not significant (p = 0.334). In the Multinational study, significantly fewer patients (14.8% of patients) on Mondeslor (Montelukast) sodium were prescribed oral corticosteroids for asthma rescue compared with patients on placebo (25.7%, p< 0.001). In the US study, 6.9% of patients on Mondeslor (Montelukast) sodium and 9.9% of patients on placebo were prescribed oral corticosteroids for asthma rescue, but the difference between the two treatment groups was not significant (p = 0.196).

Onset of Action and Maintenance of Effects

In each placebo-controlled trial in adults, the treatment effect of Mondeslor (Montelukast) sodium, measured by daily diary card parameters, including symptom scores, “as-needed” β-agonist use, and PEFR measurements, was achieved after the first dose and was maintained throughout the dosing interval (24 hours). No significant change in treatment effect was observed during continuous once-daily evening administration in non-placebo-controlled extension trials for up to one year. Withdrawal of Mondeslor (Montelukast) sodium in asthmatic patients after 12 weeks of continuous use did not cause rebound worsening of asthma.

Pediatric Patients 6 to 14 Years of Age with Asthma

The efficacy of Mondeslor (Montelukast) sodium in pediatric patients 6 to 14 years of age was demonstrated in one 8-week, double-blind, placebo-controlled trial in 336 patients (201 treated with Mondeslor (Montelukast) sodium and 135 treated with placebo) using an inhaled β-agonist on an “as-needed” basis. The patients had a mean baseline percent predicted FEV₁ of 72% (approximate range, 45 to 90%) and a mean daily inhaled β-agonist requirement of 3.4 puffs of albuterol. Approximately 36% of the patients were on inhaled corticosteroids. The median age was 11 years (range 6 to 15); 35.4% were females and 64.6% were males. The ethnic/racial distribution in this study was 80.1% Caucasian, 12.8% Black, 4.5% Hispanic, and 2.7% other origins.

Compared with placebo, treatment with one 5 mg Mondeslor (Montelukast) sodium chewable tablet daily resulted in a significant improvement in mean morning FEV₁ percent change from baseline (8.7% in the group treated with Mondeslor (Montelukast) sodium vs. 4.2% change from baseline in the placebo group, p<0.001). There was a significant decrease in the mean percentage change in daily “as-needed” inhaled β-agonist use (11.7% decrease from baseline in the group treated with Mondeslor (Montelukast) sodium vs. 8.2% increase from baseline in the placebo group, p<0.05). This effect represents a mean decrease from baseline of 0.56 and 0.23 puffs per day for the Mondeslor (Montelukast) and placebo groups, respectively. Subgroup analyses indicated that younger pediatric patients aged 6 to 11 had efficacy results comparable to those of the older pediatric patients aged 12 to 14.

Similar to the adult studies, no significant change in the treatment effect was observed during continuous once-daily administration in one open-label extension trial without a concurrent placebo group for up to 6 months.

Pediatric Patients 2 to 5 Years of Age with Asthma

The efficacy of Mondeslor (Montelukast) sodium for the chronic treatment of asthma in pediatric patients 2 to 5 years of age was explored in a 12-week, placebo-controlled safety and tolerability study in 689 patients, 461 of whom were treated with Mondeslor (Montelukast) sodium. The median age was 4 years (range 2 to 6); 41.5% were females and 58.5% were males. The ethnic/racial distribution in this study was 56.5% Caucasian, 20.9% Hispanic, 14.4% other origins, and 8.3% Black.

While the primary objective was to determine the safety and tolerability of Mondeslor (Montelukast) sodium in this age group, the study included exploratory efficacy evaluations, including daytime and overnight asthma symptom scores, β-agonist use, oral corticosteroid rescue, and the physician’s global evaluation. The findings of these exploratory efficacy evaluations, along with pharmacokinetics and extrapolation of efficacy data from older patients, support the overall conclusion that Mondeslor (Montelukast) sodium is efficacious in the maintenance treatment of asthma in patients 2 to 5 years of age.

Effects in Patients on Concomitant Inhaled Corticosteroids

Separate trials in adults evaluated the ability of Mondeslor (Montelukast) sodium to add to the clinical effect of inhaled corticosteroids and to allow inhaled corticosteroid tapering when used concomitantly.

One randomized, placebo-controlled, parallel-group trial (n=226) enrolled adults with stable asthma with a mean FEV₁ of approximately 84% of predicted who were previously maintained on various inhaled corticosteroids (delivered by metered-dose aerosol or dry powder inhalers). The median age was 41.5 years (range 16 to 70); 52.2% were females and 47.8% were males. The ethnic/racial distribution in this study was 92% Caucasian, 3.5% Black, 2.2% Hispanic, and 2.2% Asian. The types of inhaled corticosteroids and their mean baseline requirements included beclomethasone dipropionate (mean dose, 1203 mcg/day), triamcinolone acetonide (mean dose, 2004 mcg/day), flunisolide (mean dose, 1971 mcg/day), fluticasone propionate (mean dose, 1083 mcg/day), or budesonide (mean dose, 1192 mcg/day). Some of these inhaled corticosteroids were non-U.S.-approved formulations, and doses expressed may not be ex-actuator. The pre-study inhaled corticosteroid requirements were reduced by approximately 37% during a 5 to 7 week placebo run-in period designed to titrate patients toward their lowest effective inhaled corticosteroid dose. Treatment with Mondeslor (Montelukast) sodium resulted in a further 47% reduction in mean inhaled corticosteroid dose compared with a mean reduction of 30% in the placebo group over the 12 week active treatment period (p≤0.05). It is not known whether the results of this study can be generalized to patients with asthma who require higher doses of inhaled corticosteroids or systemic corticosteroids.

In another randomized, placebo-controlled, parallel-group trial (n=642) in a similar population of adult patients previously maintained, but not adequately controlled, on inhaled corticosteroids (beclomethasone 336 mcg/day), the addition of Mondeslor (Montelukast) sodium to beclomethasone resulted in statistically significant improvements in FEV₁ compared with those patients who were continued on beclomethasone alone or those patients who were withdrawn from beclomethasone and treated with Mondeslor (Montelukast) or placebo alone over the last 10 weeks of the 16-week, blinded treatment period. Patients who were randomized to treatment arms containing beclomethasone had statistically significantly better asthma control than those patients randomized to Mondeslor (Montelukast) sodium alone or placebo alone as indicated by FEV₁, daytime asthma symptoms, PEFR, nocturnal awakenings due to asthma, and “as-needed” β-agonist requirements.

In adult patients with asthma with documented aspirin sensitivity, nearly all of whom were receiving concomitant inhaled and/or oral corticosteroids, a 4-week, randomized, parallel-group trial (n=80) demonstrated that Mondeslor (Montelukast) sodium, compared with placebo, resulted in significant improvement in parameters of asthma control. The magnitude of effect of Mondeslor (Montelukast) sodium in aspirin-sensitive patients was similar to the effect observed in the general population of asthma patients studied. The effect of Mondeslor (Montelukast) sodium on the bronchoconstrictor response to aspirin or other non-steroidal anti-inflammatory drugs in aspirin-sensitive asthmatic patients has not been evaluated [see WARNINGS AND PRECAUTIONS (5.3)].

14.2 Exercise-Induced Bronchoconstriction (EIB)

Exercise-Induced Bronchoconstriction (Adults and Adolescents 15 years of age and older)

The efficacy of Mondeslor (Montelukast), 10 mg, when given as a single dose 2 hours before exercise for the prevention of EIB was investigated in three (U.S. and Multinational), randomized, double-blind, placebo-controlled crossover studies that included a total of 160 adult and adolescent patients 15 years of age and older with EIB. Exercise challenge testing was conducted at 2 hours, 8.5 or 12 hours, and 24 hours following administration of a single dose of study drug (montelukast 10 mg or placebo). The primary endpoint was the mean maximum percent fall in FEV₁ following the 2 hours post-dose exercise challenge in all three studies (Study A, Study B, and Study C). In Study A, a single dose of Mondeslor (Montelukast) sodium 10 mg demonstrated a statistically significant protective benefit against EIB when taken 2 hours prior to exercise. Some patients were protected from EIB at 8.5 and 24 hours after administration; however, some patients were not. The results for the mean maximum percent fall at each timepoint in Study A are shown in TABLE 3 and are representative of the results from the other two studies.

^*Least squares-mean

Pediatric use information for patients ages 6 to 14 years of age for acute prevention of exercise-induced bronchoconstriction (EIB) is approved for Merck Sharp & Dohme Corp’s Mondeslor (Montelukast) tablet products. However, due to Merck Sharp & Dohme Corp’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

The efficacy of Mondeslor (Montelukast) sodium for prevention of EIB in patients below 6 years of age has not been established.

Daily administration of Mondeslor (Montelukast) sodium for the chronic treatment of asthma has not been established to prevent acute episodes of EIB.

In a 12-week, randomized, double-blind, parallel group study of 110 adult and adolescent asthmatics 15 years of age and older, with a mean baseline FEV₁ percent of predicted of 83% and with documented exercise-induced exacerbation of asthma, treatment with Mondeslor (Montelukast) sodium, 10 mg, once daily in the evening, resulted in a statistically significant reduction in mean maximal percent fall in FEV₁ and mean time to recovery to within 5% of the pre-exercise FEV₁. Exercise challenge was conducted at the end of the dosing interval (i.e., 20 to 24 hours after the preceding dose). This effect was maintained throughout the 12-week treatment period indicating that tolerance did not occur. Mondeslor (Montelukast) sodium did not, however, prevent clinically significant deterioration in maximal percent fall in FEV₁ after exercise (i.e., ≥20% decrease from pre-exercise baseline) in 52% of patients studied. In a separate crossover study in adults, a similar effect was observed after two once-daily 10-mg doses of Mondeslor (Montelukast) sodium.

In pediatric patients 6 to 14 years of age, using the 5 mg chewable tablet, a 2-day crossover study demonstrated effects similar to those observed in adults when exercise challenge was conducted at the end of the dosing interval (i.e., 20 to 24 hours after the preceding dose).

14.3 Allergic Rhinitis

Seasonal Allergic Rhinitis

The efficacy of Mondeslor (Montelukast) sodium tablets for the treatment of seasonal allergic rhinitis was investigated in 5 similarly designed, randomized, double-blind, parallel-group, placebo- and active-controlled (loratadine) trials conducted in North America. The 5 trials enrolled a total of 5029 patients, of whom 1799 were treated with Mondeslor (Montelukast) sodium tablets. Patients were 15 to 82 years of age with a history of seasonal allergic rhinitis, a positive skin test to at least one relevant seasonal allergen, and active symptoms of seasonal allergic rhinitis at study entry.

The period of randomized treatment was 2 weeks in 4 trials and 4 weeks in one trial. The primary outcome variable was mean change from baseline in daytime nasal symptoms score (the average of individual scores of nasal congestion, rhinorrhea, nasal itching, sneezing) as assessed by patients on a 0 to 3 categorical scale.

Four of the five trials showed a significant reduction in daytime nasal symptoms scores with Mondeslor (Montelukast) sodium 10 mg tablets compared with placebo. The results of one trial are shown below. The median age in this trial was 35 years (range 15 to 81); 65.4% were females and 34.6% were males. The ethnic/racial distribution in this study was 83.1% Caucasian, 6.4% other origins, 5.8% Black, and 4.8% Hispanic. The mean changes from baseline in daytime nasal symptoms score in the treatment groups that received Mondeslor (Montelukast) sodium tablets, loratadine, and placebo are shown in TABLE 4. The remaining three trials that demonstrated efficacy showed similar results.

^*Average of individual scores of nasal congestion, rhinorrhea, nasal itching, sneezing as assessed by patients on a 0 to 3 categorical scale.

^†Statistically different from placebo (p≤0.001).

^‡The study was not designed for statistical comparison between Mondeslor (Montelukast) sodium and the active control (loratadine).

Perennial Allergic Rhinitis

The efficacy of Mondeslor (Montelukast) sodium tablets for the treatment of perennial allergic rhinitis was investigated in 2 randomized, double-blind, placebo-controlled studies conducted in North America and Europe. The two studies enrolled a total of 3357 patients, of whom 1632 received Mondeslor (Montelukast) sodium 10 mg tablets. Patients 15 to 82 years of age with perennial allergic rhinitis as confirmed by history and a positive skin test to at least one relevant perennial allergen (dust mites, animal dander, and/or mold spores), who had active symptoms at the time of study entry, were enrolled.

In the study in which efficacy was demonstrated, the median age was 35 years (range 15 to 81); 64.1% were females and 35.9% were males. The ethnic/racial distribution in this study was 83.2% Caucasian, 8.1% Black, 5.4% Hispanic, 2.3% Asian, and 1% other origins. Mondeslor (Montelukast) sodium 10 mg tablets once daily was shown to significantly reduce symptoms of perennial allergic rhinitis over a 6-week treatment period (TABLE 5); in this study the primary outcome variable was mean change from baseline in daytime nasal symptoms score (the average of individual scores of nasal congestion, rhinorrhea, and sneezing).

^*Average of individual scores of nasal congestion, rhinorrhea, sneezing as assessed by patients on a 0 to 3 categorical scale.

^†Statistically different from placebo (p≤0.001).

The other 6-week study evaluated Mondeslor (Montelukast) 10 mg (n=626), placebo (n=609), and an active-control (cetirizine 10 mg; n=120). The primary analysis compared the mean change from baseline in daytime nasal symptoms score for Mondeslor (Montelukast) sodium vs. placebo over the first 4 weeks of treatment; the study was not designed for statistical comparison between Mondeslor (Montelukast) sodium and the active-control. The primary outcome variable included nasal itching in addition to nasal congestion, rhinorrhea, and sneezing. The estimated difference between Mondeslor (Montelukast) sodium and placebo was -0.04 with a 95% CI of (-0.09, 0.01). The estimated difference between the active-control and placebo was -0.10 with a 95% CI of (-0.19, -0.01).

16 HOW SUPPLIED/STORAGE AND HANDLING

Mondeslor (Montelukast) sodium tablets, 10 mg are beige colored, round, biconvex, film coated tablets with "SZ 344" debossed on one side and plain on other side. They are available as follows:

NDC 0781-5560-31, bottles of 30 tablets

NDC 0781-5560-92, bottles of 90 tablets

NDC 0781-5560-13, carton of 100 tablets (10 x 10 Unit-dose)

Mondeslor (Montelukast) sodium chewable tablets, 4 mg are pink colored, round, mottled, and debossed with “SZ 74” on one side and plain on the other side. They are available as follows:

NDC 0781-5554-31, bottles of 30 tablets

NDC 0781-5554-92, bottles of 90 tablets

NDC 0781-5554-05, bottles of 500 tablets

NDC 0781-5554-64, carton of 30 tablets (3 x 10 Unit-dose)

NDC 0781-5554-13, carton of 100 tablets (10 x 10 Unit-dose)

Mondeslor (Montelukast) sodium chewable tablets, 5 mg are pink colored, round, mottled, and debossed with “SZ 76” on one side and plain on other side. They are available as follows:

NDC 0781-5555-31, bottles of 30 tablets

NDC 0781-5555-92, bottles of 90 tablets

NDC 0781-5555-05, bottles of 500 tablets

NDC 0781-5555-64, carton of 30 tablets (3 x 10 Unit-dose)

NDC 0781-5555-13, carton of 100 tablets (10 x 10 Unit-dose)

Storage

Store at 20° to 25°C (68° to 77°F). Protect from moisture and light. Store in original package.

Storage for Bulk Bottles

Store at 20° to 25°C (68° to 77°F). Protect from moisture and light. Store in original package. When product container is subdivided, repackage into a well-closed, light-resistant container.

17 PATIENT COUNSELING INFORMATION

See FDA-Approved Patient Labeling.

17.1 Information for Patients

• Patients should be advised to take Mondeslor (Montelukast) sodium daily as prescribed, even when they are asymptomatic, as well as during periods of worsening asthma, and to contact their physicians if their asthma is not well controlled.
• Patients should be advised that oral Mondeslor (Montelukast) sodium is not for the treatment of acute asthma attacks. They should have appropriate short-acting inhaled β-agonist medication available to treat asthma exacerbations. Patients who have exacerbations of asthma after exercise should be instructed to have available for rescue a short-acting inhaled β-agonist. Daily administration of Mondeslor (Montelukast) sodium for the chronic treatment of asthma has not been established to prevent acute episodes of EIB.
• Patients should be advised that, while using Mondeslor (Montelukast), sodium medical attention should be sought if short-acting inhaled bronchodilators are needed more often than usual, or if more than the maximum number of inhalations of short-acting bronchodilator treatment prescribed for a 24-hour period are needed.
• Patients receiving Mondeslor (Montelukast) sodium should be instructed not to decrease the dose or stop taking any other anti-asthma medications unless instructed by a physician.
• Patients should be instructed to notify their physician if neuropsychiatric events occur while using Mondeslor (Montelukast) sodium.
• Patients with known aspirin sensitivity should be advised to continue avoidance of aspirin or non-steroidal anti-inflammatory agents while taking Mondeslor (Montelukast) sodium.
• Phenylketonuric patients should be informed that the 4-mg and 5-mg chewable tablets contain phenylalanine (a component of aspartame).

Patient Information

Mondeslor (Montelukast) Sodium Tablets

Read the Patient Information Leaflet that comes with Mondeslor (Montelukast) sodium before you start taking it and each time you get a refill. There may be new information. This leaflet does not take the place of talking with your healthcare provider about your medical condition or your treatment.

What is Mondeslor (Montelukast) sodium?

• Mondeslor (Montelukast) sodium is a prescription medicine that blocks substances in the body called leukotrienes. This may help to improve symptoms of asthma and allergic rhinitis. Mondeslor (Montelukast) sodium does not contain a steroid.

Mondeslor (Montelukast) sodium is used to:

• Prevent asthma attacks and for the long-term treatment of asthma in adults and children ages 2 years and older.
  

  Do not take Mondeslor (Montelukast) sodium if you need relief right away for a sudden asthma attack. If you get an asthma attack, you should follow the instructions your healthcare provider gave you for treating asthma attacks.
  

• Prevent exercise-induced asthma in people 15 years of age and older.
• Help control the symptoms of allergic rhinitis (sneezing, stuffy nose, runny nose, itching of the nose). Mondeslor (Montelukast) sodium is used to treat:
  • outdoor allergies that happen part of the year (seasonal allergic rhinitis) in adults and children ages 2 years and older, and
  • indoor allergies that happen all year (perennial allergic rhinitis) in adults and children ages 2 years and older.

Who should not take Mondeslor (Montelukast) sodium?

Do not take Mondeslor (Montelukast) sodium if you are allergic to any of its ingredients.

See the end of this leaflet for a complete list of the ingredients in Mondeslor (Montelukast) sodium.

What should I tell my healthcare provider before taking Mondeslor (Montelukast) sodium?

Before taking Mondeslor (Montelukast) sodium, tell your healthcare provider if you:

• are allergic to aspirin
• have phenylketonuria. Mondeslor (Montelukast) sodium chewable tablets contain aspartame, a source of phenylalanine
• have any other medical conditions
• are pregnant or plan to become pregnant. If you are pregnant or plan to become pregnant, Mondeslor (Montelukast) sodium may not be right for you.
• are breast-feeding or plan to breast-feed. It is not known if Mondeslor (Montelukast) sodium passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby while taking Mondeslor (Montelukast) sodium.

Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Some medicines may affect how Mondeslor (Montelukast) sodium works, or Mondeslor (Montelukast) sodium may affect how your other medicines work.

How should I take Mondeslor (Montelukast) sodium?

For anyone who takes Mondeslor (Montelukast) sodium:

• Take Mondeslor (Montelukast) sodium exactly as prescribed by your healthcare provider. Your healthcare provider will tell you how much Mondeslor (Montelukast) sodium to take, and when to take it.
• Do not stop taking Mondeslor (Montelukast) sodium or change when you take it without talking with your healthcare provider.
• You can take Mondeslor (Montelukast) sodium with food or without food.
• If you or your child misses a dose of Mondeslor (Montelukast) , sodium just take the next dose at your regular time. Do not take 2 doses at the same time.
• If you take too much Mondeslor (Montelukast) sodium call your doctor.

For adults and children 2 years of age and older with asthma:

• Take Mondeslor (Montelukast) sodium one time each day, in the evening. Continue to take Mondeslor (Montelukast) sodium every day for as long as your healthcare provider prescribes it, even if you have no asthma symptoms.
• Tell your healthcare provider right away if your asthma symptoms get worse, or if you need to use your rescue inhaler medicine more often for asthma attacks.
• Do not take Mondeslor (Montelukast) sodium if you need relief right away from a sudden asthma attack. If you get an asthma attack, you should follow the instructions your healthcare provider gave you for treating asthma attacks.
• Always have your rescue inhaler medicine with you for asthma attacks.
• Do not stop taking or lower the dose of your other asthma medicines unless your healthcare provider tells you to.

For patients 15 years of age and older for the prevention of exercise-induced asthma:

• Take Mondeslor (Montelukast) sodium at least 2 hours before exercise.
• Always have your rescue inhaler medicine with you for asthma attacks.
• If you take Mondeslor (Montelukast) sodium every day for chronic asthma or allergic rhinitis, do not take another dose to prevent exercise-induced asthma. Talk to your healthcare provider about your treatment for exercise-induced asthma.
• Do not take 2 doses of Mondeslor (Montelukast) within 24 hours (1 day).

For adults and children 2 years of age and older with seasonal allergic rhinitis, or for adults and children 2 years of age and older with perennial allergic rhinitis:

• Take Mondeslor (Montelukast) sodium one time each day, at about the same time each day.

What is the dose of Mondeslor (Montelukast) sodium?

The dose of Mondeslor (Montelukast) sodium prescribed for your or your child's condition is based on age:

• 2 to 5 years: one 4 mg chewable tablet
• 6 to 14 years: one 5 mg chewable tablet.
• 15 years and older: one 10 mg tablet.

What should I avoid while taking Mondeslor (Montelukast) sodium?

If you have asthma and aspirin makes your asthma symptoms worse, continue to avoid taking aspirin or other medicines called non-steroidal anti-inflammatory drugs (NSAIDs) while taking Mondeslor (Montelukast) sodium.

What are the possible side effects of Mondeslor (Montelukast) sodium?

Mondeslor (Montelukast) sodium may cause serious side effects.

• Behavior and mood-related changes. Tell your healthcare provider right away if you or your child have any of these symptoms while taking Mondeslor (Montelukast) sodium:
• agitation including aggressive behavior or hostility
• bad or vivid dreams
• depression
• disorientation (confusion)
• feeling anxious
• hallucinations (seeing or hearing things that are not really there)
• irritability
• restlessness
• sleep walking
• suicidal thoughts and actions (including suicide)
• tremor
• trouble sleeping
• Increase in certain white blood cells ( eosinophils ) and possible inflamed blood vessels throughout the body (systemic vasculitis ). Rarely, this can happen in people with asthma who take Mondeslor (Montelukast) sodium. This usually, but not always, happens in people who also take a steroid medicine by mouth that is being stopped or the dose is being lowered.
• Tell your healthcare provider right away if you get one or more of these symptoms:
  • a feeling of pins and needles or numbness of arms or legs
  • a flu-like illness
  • rash
  • severe inflammation (pain and swelling) of the sinuses (sinusitis)

The most common side effects with Mondeslor (Montelukast) sodium include:

• upper respiratory infection
• fever
• headache
• sore throat
• cough
• stomach pain
• diarrhea
• earache or ear infection
• flu
• runny nose
• sinus infection

Other side effects with Mondeslor (Montelukast) sodium include:

• increased bleeding tendency, low blood platelet count
• allergic reactions [including swelling of the face, lips, tongue, and/or throat (which may cause trouble breathing or swallowing), hives and itching]
• dizziness, drowsiness, pins and needles/numbness, seizures (convulsions or fits)
• palpitations
• nose bleed, stuffy nose
• diarrhea, heartburn, indigestion, inflammation of the pancreas, nausea, stomach or intestinal upset, vomiting
• hepatitis
• bruising, rash
• joint pain, muscle aches and muscle cramps
• tiredness, swelling

Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects of Mondeslor (Montelukast) sodium. For more information ask your healthcare provider or pharmacist.

Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store Mondeslor (Montelukast) sodium?

• Store Mondeslor (Montelukast) sodium at 20° to 25°C (68° to 77°F).
• Keep Mondeslor (Montelukast) sodium in the container it comes in.
• Keep Mondeslor (Montelukast) sodium in a dry place and away from light.

General information about the safe and effective use of Mondeslor (Montelukast) sodium

Medicines are sometimes prescribed for purposes other than those mentioned in Patient Information Leaflets. Do not use Mondeslor (Montelukast) sodium for a condition for which it was not prescribed. Do not give Mondeslor (Montelukast) sodium to other people even if they have the same symptoms you have. It may harm them. Keep Mondeslor (Montelukast) sodium and all medicines out of the reach of children.

This leaflet summarizes information about Mondeslor (Montelukast) sodium. If you would like more information, talk to your healthcare provider. You can ask your pharmacist or healthcare provider for information about Mondeslor (Montelukast) sodium that is written for health professionals. For more information, call Sandoz Inc. at 1-800-525-8747.

What are the ingredients in Mondeslor (Montelukast) sodium?

Active ingredient: Mondeslor (Montelukast) sodium

Inactive ingredients:

10 mg tablet: croscarmellose sodium, hydroxypropyl cellulose, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, red ferric oxide, titanium dioxide, and yellow ferric oxide.

4 mg and 5 mg chewable tablets: artificial cherry durarome flavor, aspartame, cherry flavor croscarmellose sodium, hydroxypropyl cellulose, magnesium stearate, mannitol, microcrystalline cellulose, and red ferric oxide.

The artificial cherry durarome flavor contain: artificial flavors, maltodextrin, red # 40, silicon dioxide, soy lecithin and sugar.

The cherry flavor contain: artificial flavors, benzyl alcohol, lactic acid, and maltodextrin.

Pediatric use information for patients ages 6 to 14 years of age for prevention of exercise-induced asthma is approved for Merck Sharp & Dohme Corp’s Mondeslor (Montelukast) tablet products. However, due to Merck Sharp & Dohme Corp’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

Manufactured in India by Sandoz Private Ltd.

for Sandoz Inc., Princeton, NJ 08540

Rev. July 2012

Mondeslor (Montelukast) Sodium 10mg Tablet

Figure 1: Change in Height (cm) Structural Formula Figure 2