Levocetirizine

IT IS A LONG ACTING HISTAMINE, H1 RECEPTOR ANTAGONIST AND SHOWS POOR PENETRATION INTO CNS.

Dose:

5 MG ONCE DAILY

Monography

*************************** Entire Monograph *************************** DESCRIPTION: Levocetirizine hydrochloride, the active component of STARCET tablets and syrup, is an orally active and selective H1-receptor antagonist. The chemical name is ()-(2-(4-((4-chlorophenyl)phenylmethyl)-1- piperazinyl)ethoxy)acetic acid, dihydrochloride. Levocetirizine hydrochloride is a racemic compound with an empirical formula of C21H25ClN2O3--2HCl. The molecular weight is 461.82. Levocetirizine hydrochloride is a white, crystalline powder and is water soluble. STARCET tablets are formulated as white, film-coated, rounded-off rectangular shaped tablets for oral administration and are available in 5 mg strengths. Inactive ingredients are: lactose; magnesium stearate; povidone; titanium dioxide; hydroxypropyl methylcellulose; polyethylene glycol; and corn starch. ACTIONS/CLINICAL PHARMACOLOGY: MECHANISM OF ACTIONS: Levocetirizine, a human metabolite of hydroxyzine, is an antihistamine; its principal effects are mediated via selective inhibition of peripheral H1 receptors. The antihistaminic activity of levocetirizine has been clearly documented in a variety of animal and human models. In Vivo and Ex Vivo animal models have shown negligible anticholinergic and antiserotonergic activity. In clinical studies, however, dry mouth was more common with levocetirizine than with placebo. In Vitro receptor binding studies have shown no measurable affinity for other than H1 receptors. Autoradiographic studies with radiolabeled levocetirizine in the rat have shown negligible penetration into the brain. Ex Vivo experiments in the mouse have shown that systemically administered levocetirizine does not significantly occupy cerebral H1 receptors. PHARMACOKINETICS: ABSORPTION: Levocetirizine was rapidly absorbed with a time to maximum concentration (Tmax) of approximately 1 hour following oral administration of tablets or syrup in adults. Comparable bioavailability was found between the tablet and syrup dosage forms. When healthy volunteers were administered multiple doses of levocetirizine (10 mg tablets once daily for 10 days), a mean peak plasma concentration (Cmax) of 311 ng/mL was observed. No accumulation was observed. Levocetirizine pharmacokinetics were linear for oral doses ranging from 5 to 60 mg. Food had no effect on the extent of levocetirizine exposure (AUC) but Tmax was delayed by 1.7 hours and Cmax was decreased by 23% in the presence of food. DISTRIBUTION: The mean plasma protein binding of levocetirizine is 93%, independent of concentration in the range of 25-1000 ng/mL, which includes the therapeutic plasma levels observed. METABOLISM: A mass balance study in 6 healthy male volunteers indicated that 70% of the administered radioactivity was recovered in the urine and 10% in the feces. Approximately 50% of the radioactivity was identified in the urine as unchanged drug. Most of the rapid increase in peak plasma radioactivity was associated with parent drug, suggesting a low degree of first- pass metabolism. Levocetirizine is metabolized to a limited extent by oxidative O-dealkylation to a metabolite with negligible antihistaminic activity. The enzyme or enzymes responsible for this metabolism have not been identified. ELIMINATION: The mean elimination half-life in 146 healthy volunteers across multiple pharmacokinetic studies was 8.3 hours and the apparent total body clearance for levocetirizine was approximately 53 mL/min. INTERACTION STUDIES Pharmacokinetic interaction studies with levocetirizine in adults were conducted with pseudoephedrine, antipyrine, ketoconazole, erythromycin and azithromycin. No interactions were observed. In a multiple dose study of theophylline (400 mg once daily for 3 days) and levocetirizine (20 mg once daily for 3 days), a 16% decrease in the clearance of levocetirizine was observed. The disposition of theophylline was not altered by concomitant levocetirizine administration. SPECIAL POPULATIONS PEDIATRIC PATIENTS: When pediatric patients aged 7 to 12 years received a single, 5-mg oral levocetirizine capsule, the mean Cmax was 275 ng/mL. Based on cross-study comparisons, the weight- normalized, apparent total body clearance was 33% greater and the elimination half-life was 33% shorter in this pediatric population than in adults. In pediatric patients aged 2 to 5 years who received 5 mg of levocetirizine, the mean Cmax was 660 ng/mL. Based on cross-study comparisons, the weight-normalized apparent total body clearance was 81 to 111% greater and the elimination half-life was 33 to 41% shorter in this pediatric population than in adults. GERIATRIC PATIENTS: Following a single, 10-mg oral dose, the elimination half- life was prolonged by 50% and the apparent total body clearance was 40% lower in 16 geriatric subjects with a mean age of 77 years compared to 14 adult subjects with a mean age of 53 years. The decrease in levocetirizine clearance in these elderly volunteers may be related to decreased renal function. EFFECT OF GENDER: The effect of gender on levocetirizine pharmacokinetics has not been adequately studied. EFFECT OF RACE: No race-related differences in the kinetics of levocetirizine have been observed. RENAL IMPAIRMENT: The kinetics of levocetirizine were studied following multiple, oral, 10-mg daily doses of levocetirizine for 7 days in 7 normal volunteers (creatinine clearance 89-128 mL/min), 8 patients with mild renal function impairment (creatinine clearance 42-77 mL/min) and 7 patients with moderate renal function impairment (creatinine clearance 11-31 mL/min). The pharmacokinetics of levocetirizine were similar in patients with mild impairment and normal volunteers. Moderately impaired patients had a 3-fold increase in half- life and a 70% decrease in clearance compared to normal volunteers. Patients on hemodialysis (n=5) given a single, 10-mg dose of levocetirizine had a 3- fold increase in half-life and a 70% decrease in clearance compared to normal volunteers. Less than 10% of the administered dose was removed during the single dialysis session. Dosing adjustment is necessary in patients with moderate or severe renal impairment and in patients on dialysis (see DOSAGE AND ADMINISTRATION). HEPATIC IMPAIRMENT: Sixteen patients with chronic liver diseases (hepatocellular, cholestatic, and biliary cirrhosis), given 10 to 20 mg of levocetirizine as a single, oral dose had a 50% increase in half-life along with a corresponding 40% decrease in clearance compared to 16 healthy subjects. Dosing adjustment may be necessary in patients with hepatic impairment (see DOSAGE AND ADMINISTRATION). PHARMACODYNAMICS: Studies in 69 adult normal volunteers (aged 20 to 61 years) showed that STARCET at doses of 5 and 10 mg strongly inhibited the skin wheal and flare caused by the intradermal injection of histamine. The onset of this activity after a single 10-mg dose occurred within 20 minutes in 50% of subjects and within one hour in 95% of subjects; this activity persisted for at least 24 hours. STARCET at doses of 5 and 10 mg also strongly inhibited the wheal and flare caused by intradermal injection of histamine in 19 pediatric volunteers (aged 5 to 12 years) and the activity persisted for at least 24 hours. In a 35- day study in children aged 5 to 12, no tolerance to the antihistaminic (suppression of wheal and flare response) effects of STARCET was found. The effects of intradermal injection of various other mediators or histamine releasers were also inhibited by levocetirizine, as was response to a cold challenge in patients with cold-induced urticaria. In mildly asthmatic subjects, STARCET at 5 to 20 mg blocked bronchoconstriction due to nebulized histamine, with virtually total blockade after a 20-mg dose. In studies conducted for up to 12 hours following cutaneous antigen challenge, the late phase recruitment of eosinophils, neutrophils and basophils, components of the allergic inflammatory response, was inhibited by STARCET at a dose of 20 mg. In four clinical studies in healthy adult males, no clinically significant mean increases in QTc were observed in STARCET treated subjects. In the first study, a placebo-controlled crossover trial, STARCET was given at doses up to 60 mg per day, 6 times the maximum clinical dose, for 1 week, and no significant mean QTc prolongation occurred. In the second study, a crossover trial, STARCET 20 mg and erythromycin (500 mg every 8 hours) were given alone and in combination. There was no significant effect on QTc with the combination or with STARCET alone. In the third trial, also a crossover study, STARCET 20 mg and ketoconazole (400 mg per day) were given alone and in combination. STARCET caused a mean increase in QTc of 9.1 msec from baseline after 10 days of therapy. Ketoconazole also increased QTc by 8.3 msec. The combination caused an increase of 17.4 msec, equal to the sum of the individual effects. Thus, there was no significant drug interaction on QTc with the combination of STARCET and ketoconazole. In the fourth study, a placebo- controlled parallel trial, STARCET 20 mg was given alone or in combination with azithromycin (500 mg as a single dose on the first day followed by 250mg once daily). There was no significant increase in OTc with STARCET 20 mg alone or in combination with azithromycin. In a four-week clinical trial in pediatric patients aged 6 to 11 years, results of randomly obtained ECG measurements before treatment and after 2 weeks of treatment showed that STARCET 5 or 10 mg did not significantly increase QTc versus placebo. The effects of STARCET on the QTc interval at doses higher than the 10 mg dose have not been studied in children less than 12 years of age. The effect of STARCET on the QTc interval in children less than 6 years of age has not been studied. In a six-week, placebo-controlled study of 186 patients (aged 12 to 64 years) with allergic rhinitis and mild to moderate asthma, STARCET 10 mg once daily improved rhinitis symptoms and did not alter pulmonary function. In a two-week, placebo-controlled clinical trial, a subset analysis of 65 pediatric (aged 6 to 11 years) allergic rhinitis patients with asthma showed STARCET did not alter pulmonary function. These studies support the safety of administering STARCET to pediatric and adult allergic rhinitis patients with mild to moderate asthma. CLINICAL STUDIES: Nine multicenter, randomized, double-blind, clinical trials comparing levocetirizine 5 to 20 mg to placebo in patients 12 years and older with seasonal or perennial allergic rhinitis were conducted in the United States. Five of these showed significant reductions in symptoms of allergic rhinitis, 3 in seasonal allergic rhinitis (1 to 4 weeks in duration) and 2 in perennial allergic rhinitis for up to 8 weeks in duration. Two 4-week multicenter, randomized, double-blind, clinical trials comparing levocetirizine 5 to 20 mg to placebo in patients with chronic idiopathic urticaria were also conducted and showed significant improvement in symptoms of chronic idiopathic urticaria. In general, the 10-mg dose was more effective than the 5-mg dose and the 20-mg dose gave no added effect. Some of these trials included pediatric patients aged 12 to 16 years. In addition, four multicenter, randomized, placebo-controlled, double-blind 2-4 week trials in 534 pediatric patients aged 6 to 11 years with seasonal allergic rhinitis were conducted in the United States at doses up to 10 mg. INDICATIONS AND USAGE: SEASONAL ALLERGIC RHINITIS: STARCET is indicated for the relief of symptoms associated with seasonal allergic rhinitis due to allergens such as ragweed, grass and tree pollens in adults and children 2 years of age and older. Symptoms treated effectively include sneezing, rhinorrhea, nasal pruritus, ocular pruritus, tearing, and redness of the eyes. PERENNIAL ALLERGIC RHINITIS: STARCET is indicated for the relief of symptoms associated with perennial allergic rhinitis due to allergens such as dust mites, animal dander and molds in adults and children 2 years of age and older. Symptoms treated effectively include sneezing, rhinorrhea, postnasal discharge, nasal pruritus, ocular pruritus, and tearing. CHRONIC URTICARIA: STARCET is indicated for the treatment of the uncomplicated skin manifestations of chronic idiopathic urticaria in adults and children 2 years of age and older. It significantly reduces the occurrence, severity, and duration of hives and significantly reduces pruritus. CONTRAINDICATIONS: STARCET is contraindicated in those patients with a known hypersensitivity to it or any of its ingredients or hydroxyzine. PRECAUTIONS: ACTIVITIES REQUIRING MENTAL ALERTNESS: In clinical trials, the occurrence of somnolence has been reported in some patients taking STARCET; due caution should therefore be exercised when driving a car or operating potentially dangerous machinery. Concurrent use of STARCET with alcohol or other CNS depressants should be avoided because additional reductions in alertness and additional impairment of CNS performance may occur. DRUG-DRUG INTERACTIONS: No clinically significant drug interactions have been found with theophylline at a low dose, azithromycin, pseudoephedrine, ketoconazole, or erythromycin. There was a small decrease in the clearance of levocetirizine caused by a 400-mg dose of theophylline; it is possible that larger theophylline doses could have a greater effect. CARCINOGENESIS, MUTAGENESIS AND IMPAIRMENT OF FERTILITY: In a 2-year carcinogenicity study in rats, levocetirizine was not carcinogenic at dietary doses up to 20 mg/kg (approximately 15 times the maximum recommended daily oral dose in adults on a mg/m(squared) basis, or approximately 10 times the maximum recommended daily oral dose in children on a mg/m(squared) basis). In a 2-year carcinogenicity study in mice, levocetirizine caused an increased incidence of benign liver tumors in males at a dietary dose of 16 mg/kg (approximately 6 times the maximum recommended daily oral dose in adults on a mg/m(squared) basis, or approximately 4 times the maximum recommended daily oral dose in children on a mg/m(squared) basis). No increase in the incidence of liver tumors was observed in mice at a dietary dose of 4 mg/kg (approximately 2 times the maximum recommended daily oral dose in adults on a mg/m(squared) basis, or approximately equal to the maximum recommended daily oral dose in children on a mg/m(squared) basis). The clinical significance of these findings during long- term use of STARCET is not known. Levocetirizine was not mutagenic in the Ames test, and not clastogenic in the human lymphocyte assay, the mouse lymphoma assay, and In Vivo micronucleus test in rats. In a fertility and general reproductive performance study in mice, levocetirizine did not impair fertility at an oral dose of 64 mg/kg (approximately 25 times the maximum recommended daily oral dose in adults on a mg/m(squared) basis). PREGNANCY CATEGORY B: In mice, rats, and rabbits, levocetirizine was not teratogenic at oral doses up to 96, 225, and 135 mg/kg, respectively (approximately 40, 180 and 220 times the maximum recommended daily oral dose in adults on a mg/m(squared) basis). There are no adequate and well-controlled studies in pregnant women. Because animal studies are not always predictive of human response, STARCET should be used in pregnancy only if clearly needed. NURSING MOTHERS: In mice, levocetirizine caused retarded pup weight gain during lactation at an oral dose in dams of 96 mg/kg (approximately 40 times the maximum recommended daily oral dose in adults on a mg/m(squared) basis). Studies in beagle dogs indicated that approximately 3% of the dose was excreted in milk. Levocetirizine has been reported to be excreted in human breast milk. Because many drugs are excreted in human milk, use of STARCET in nursing mothers is not recommended. GERIATRIC USE: In placebo-controlled trials, 186 patients aged 65 to 94 years received doses of 5 to 20 mg of STARCET per day. Adverse events were similar in this group to patients under age 65. Subset analysis of efficacy in this group was not done. PEDIATRIC USE: The safety of STARCET, at daily doses of 5 or 10 mg, has been demonstrated in 376 pediatric patients aged 6 to 11 years in placebo- controlled trials lasting up to four weeks and in 254 patients in a non-placebo-controlled 12-week trial. The safety of levocetirizine has been demonstrated in 168 patients aged 2 to 5 years in placebo-controlled trials of up to 4 weeks duration. On a mg/kg basis, most of the 168 patients received between 0.2 and 0.4 mg/kg of levocetirizine HCl. The effectiveness of STARCET for the treatment of seasonal and perennial allergic rhinitis and chronic idiopathic urticaria in pediatric patients aged 2 to 11 years is based on an extrapolation of the demonstrated efficacy of STARCET in adults in these conditions and the likelihood that the disease course, pathophysiology and the drug's effect are substantially similar between these two populations. The recommended doses for the pediatric population are based on cross-study comparisons of the pharmacokinetics and pharmacodynamics of levocetirizine in adult and pediatric subjects and on the safety profile of levocetirizine in both adult and pediatric patients at doses equal to or higher than the recommended doses. The levocetirizine AUC and Cmax in pediatric subjects aged 2 to 5 years who received a single dose of 5 mg of levocetirizine syrup and in pediatric subjects aged 6 to 11 years who received a single dose of 10 mg of levocetirizine syrup were estimated to be intermediate between that observed in adults who received a single dose of 10 mg of levocetirizine tablets and those who received a single dose of 20 mg of levocetirizine tablets. The safety and effectiveness of levocetirizine in pediatric patients under the age of 2 years have not yet been established. DRUG INTERACTIONS: No clinically significant drug interactions have been found with theophylline at a low dose, azithromycin, pseudoephedrine, ketoconazole, or erythromycin. There was a small decrease in the clearance of levocetirizine caused by a 400-mg dose of theophylline; it is possible that larger theophylline doses could have a greater effect. (See Also PRECAUTIONS.) ADVERSE REACTIONS: Controlled and uncontrolled clinical trials conducted in the United States and Canada included more than 6000 patients aged 12 years and older, with more than 3900 receiving STARCET at doses of 5 to 20 mg per day. The duration of treatment ranged from 1 week to 6 months, with a mean exposure of 30 days. Most adverse reactions reported during therapy with STARCET were mild or moderate. In placebo- controlled trials, the incidence of discontinuations due to adverse reactions in patients receiving STARCET 5 or 10 mg was not significantly different from placebo (2.9% vs. 2.4%, respectively). The most common adverse reaction in patients aged 12 years and older that occurred more frequently on STARCET than placebo was somnolence. The incidence of somnolence associated with STARCET was dose related, 6% in placebo, 11% at 5 mg and 14% at 10 mg. Discontinuations due to somnolence for STARCET were uncommon (1.0% on STARCET vs. 0.6% on placebo). Fatigue and dry mouth also appeared to be treatment-related adverse reactions. There were no differences by age, race, gender or by body weight with regard to the incidence of adverse reactions. Table 1 lists adverse experiences in patients aged 12 years and older which were reported for STARCET 5 and 10 mg in controlled clinical trials in the United States and that were more common with STARCET than placebo. TABLE 1. ADVERSE EXPERIENCES REPORTED IN PATIENTS AGED 12 YEARS AND OLDER IN PLACEBO-CONTROLLED UNITED STATES STARCET TRIALS (MAXIMUM DOSE OF 10 MG) AT RATES OF 2% OR GREATER (PERCENT INCIDENCE) ADVERSE STARCET PLACEBO EXPERIENCE (N=2034) (N=1612) Somnolence 13.7 6.3 Fatigue 5.9 2.6 Dry Mouth 5.0 2.3 Pharyngitis 2.0 1.9 Dizziness 2.0 1.2 In addition, headache and nausea occurred in more than 2% of the patients, but were more common in placebo patients. Pediatric studies were also conducted with STARCET. More than 1300 pediatric patients aged 6 to 11 years with more than 900 treated with STARCET at doses of 1.25 to 10 mg per day were included in controlled and uncontrolled clinical trials conducted in the United States. The duration of treatment ranged from 2 to 12 weeks. Placebo-controlled trials up to 4 weeks duration included 168 pediatric patients aged 2 to 5 years who received levocetirizine, the majority of whom received single daily doses of 5 mg. The majority of adverse reactions reported in pediatric patients aged 2 to 11 years with STARCET were mild or moderate. In placebo-controlled trials, the incidence of discontinuations due to adverse reactions in pediatric patients receiving up to 10 mg of STARCET was uncommon (0.4% on STARCET vs. 1.0% on placebo). Table 2 lists adverse experiences which were reported for STARCET 5 and 10 mg in pediatric patients aged 6 to 11 years in placebo-controlled clinical trials in the United States and were more common with STARCET than placebo. Of these, abdominal pain was considered treatment-related and somnolence appeared to be dose-related, 1.3% in placebo, 1.9% at 5 mg and 4.2% at 10 mg. The adverse experiences reported in pediatric patients aged 2 to 5 years in placebo- controlled trials were qualitatively similar in nature and generally similar in frequency to those reported in trials with children aged 6 to 11 years. TABLE 2. ADVERSE EXPERIENCES REPORTED IN PEDIATRIC PATIENTS AGED 6 TO 11 YEARS IN PLACEBO-CONTROLLED UNITED STATES STARCET TRIALS (5 OR 10 MG DOSE) WHICH OCCURRED AT A FREQUENCY OF (>/=)2% IN EITHER THE 5-MG OR THE 10-MG STARCET GROUP, AND MORE FREQUENTLY THAN IN THE PLACEBO GROUP STARCET ADVERSE EXPERIENCES PLACEBO 5 MG 10 MG (N=309) (N=161) (N=215) Headache 12.3% 11.0% 14.0% Pharyngitis 2.9% 6.2% 2.8% Abdominal pain 1.9% 4.4% 5.6% Coughing 3.9% 4.4% 2.8% Somnolence 1.3% 1.9% 4.2% Diarrhea 1.3% 3.1% 1.9% Epistaxis 2.9% 3.7% 1.9% Bronchospasm 1.9% 3.1% 1.9% Nausea 1.9% 1.9% 2.8% Vomiting 1.0% 2.5% 2.3% The following events were observed infrequently (less than 2%), in either 3982 adults and children 12 years and older or in 659 pediatric patients aged 6 to 11 years who received STARCET in U.S. trials, including an open adult study of six months duration. A causal relationship of these infrequent events with STARCET administration has not been established. AUTONOMIC NERVOUS SYSTEM: anorexia, flushing, increased salivation, urinary retention. CARDIOVASCULAR: cardiac failure, hypertension, palpitation, tachycardia. CENTRAL AND PERIPHERAL NERVOUS SYSTEMS: abnormal coordination, ataxia, confusion, dysphonia, hyperesthesia, hyperkinesia, hypertonia, hypoesthesia, leg cramps, migraine, myelitis, paralysis, paresthesia, ptosis, syncope, tremor, twitching, vertigo, visual field defect. GASTROINTESTINAL: abnormal hepatic function, aggravated tooth caries, constipation, dyspepsia, eructation, flatulence, gastritis, hemorrhoids, increased appetite, melena, rectal hemorrhage, stomatitis including ulcerative stomatitis, tongue discoloration, tongue edema. GENITOURINARY: cystitis, dysuria, hematuria, micturition frequency, polyuria, urinary incontinence, urinary tract infection. HEARING AND VESTIBULAR: deafness, earache, ototoxicity, tinnitus. METABOLIC/NUTRITIONAL: dehydration, diabetes mellitus, thirst. MUSCULOSKELETAL: arthralgia, arthritis, arthrosis, muscle weakness, myalgia. PSYCHIATRIC: abnormal thinking, agitation, amnesia, anxiety, decreased libido, depersonalization, depression, emotional lability, euphoria, impaired concentration, insomnia, nervousness, paroniria, sleep disorder. RESPIRATORY SYSTEM: bronchitis, dyspnea, hyperventilation, increased sputum, pneumonia, respiratory disorder, rhinitis, sinusitis, upper respiratory tract infection. REPRODUCTIVE: dysmenorrhea, female breast pain, intermenstrual bleeding, leukorrhea, menorrhagia, vaginitis. RETICULOENDOTHELIAL: lymphadenopathy. SKIN: acne, alopecia, angioedema, bullous eruption, dermatitis, dry skin, eczema, erythematous rash, furunculosis, hyperkeratosis, hypertrichosis, increased sweating, maculopapular rash, photosensitivity reaction, photosensitivity toxic reaction, pruritus, purpura, rash, seborrhea, skin disorder, skin nodule, urticaria. SPECIAL SENSES: parosmia, taste loss, taste perversion. VISION: blindness, conjunctivitis, eye pain, glaucoma, loss of accommodation, ocular hemorrhage, xerophthalmia. BODY AS A WHOLE: accidental injury, asthenia, back pain, chest pain, enlarged abdomen, face edema, fever, generalized edema, hot flashes, increased weight, leg edema, malaise, nasal polyp, pain, pallor, periorbital edema, peripheral edema, rigors. Occasional instances of transient, reversible hepatic transaminase elevations have occurred during levocetirizine therapy. Hepatitis with significant transaminase elevation and elevated bilirubin in association with the use of STARCET has been reported. In foreign marketing experience the following additional rare, but potentially severe adverse events have been reported: anaphylaxis, cholestasis, glomerulonephritis, hemolytic anemia, hepatitis, orofacial dyskinesia, severe hypotension, stillbirth, and thrombocytopenia. DRUG ABUSE AND DEPENDENCE: There is no information to indicate that abuse or dependency occurs with STARCET. OVERDOSAGE: Overdosage has been reported with STARCET. In one adult patient who took 150 mg of STARCET, the patient was somnolent but did not display any other clinical signs or abnormal blood chemistry or hematology results. In an 18 month old pediatric patient who took an overdose of STARCET (approximately 180 mg), restlessness and irritability were observed initially; this was followed by drowsiness. Should overdose occur, treatment should be symptomatic or supportive, taking into account any concomitantly ingested medications. There is no known specific antidote to STARCET. STARCET is not effectively removed by dialysis, and dialysis will be ineffective unless a dialyzable agent has been concomitantly ingested. The acute minimal lethal oral doses were 237 mg/kg in mice (approximately 95 times the maximum recommended daily oral dose in adults on a mg/m(squared) basis, or approximately 55 times the maximum recommended daily oral dose in children on a mg/m(squared) basis) and 562 mg/kg in rats (approximately 460 times the maximum recommended daily oral dose in adults on a mg/m(squared) basis, or approximately 270 times the maximum recommended daily oral dose in children on a mg/m(squared) basis). In rodents, the target of acute toxicity was the central nervous system, and the target of multiple-dose toxicity was the liver. DOSAGE AND ADMINISTRATION: ADULTS AND CHILDREN 12 YEARS AND OLDER: The recommended initial dose of STARCET is 5 or 10 mg per day in adults and children 12 years and older, depending on symptom severity. Most patients in clinical trials started at 10 mg. STARCET is given as a single daily dose, with or without food. The time of administration may be varied to suit individual patient needs. CHILDREN 6 TO 11 YEARS: The recommended initial dose of STARCET in children aged 6 to 11 years is 5 or 10 mg (1 or 2 teaspoons) once daily depending on symptom severity. The time of administration may be varied to suit individual patient needs. CHILDREN 2 TO 5 YEARS: The recommended initial dose of STARCET syrup in children aged 2 to 5 years is 2.5 mg ( 1/2 teaspoon) once daily. The dosage in this age group can be increased to a maximum dose of 5 mg per day given as 1 teaspoon (5 mg) once daily, or as 1/2 teaspoon (2.5 mg) given every 12 hours, depending on symptom severity and patient response. DOSE ADJUSTMENT FOR RENAL AND HEPATIC IMPAIRMENT: In patients 12 years of age and older with decreased renal function (creatinine clearance 11-31 mL/min), patients on hemodialysis (creatinine clearance less than 7 mL/min), and in hepatically impaired patients, a dose of 5 mg once daily is recommended. Similarly, pediatric patients aged 6 to 11 years with impaired renal or hepatic function should use the lower recommended dose. Because of the difficulty in reliably administering doses of less than 2.5 mg ( 1/2 teaspoon) of STARCET syrup and in the absence of pharmacokinetic and safety information for levocetirizine in children below the age of 6 years with impaired renal or hepatic function, its use in this impaired patient population is not recommended.

MONTELUKAST SODIUM

IT IS A SELECTIVE AND ORALLY ACTIVE LEUKOTRIENE RECEPTOR ANTAGONIST THAT INHIBITS THE CYSTEINYL LEUKOTRIENE CYSLT-1 RECEPTOR.MONTELUKAST INHIBITS PHYSIOLOGIC ACTION OF LTD-4 AT THE CYSLT-1 RECEPTOR WITHOUT ANY AGONIST ACTIVITY.

Dose

ADULT - 10 MG DAILY IN THE EVENING 6-14 YRS - 5 MG TAB DAILY 2-5 YRS - 4 MG TAB ONCE DAILY

Monography

MONTELUKAST SODIUM DESCRIPTION Montelukast sodium, the active ingredient in MONTAIR*, is a selective and orally active leukotriene receptor antagonist that inhibits the cysteinyl leukotriene CysLT 1 receptor Montelukast sodium is described chemically as [R-(E)]-1-[[[1-[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3- [2-(1-hydroxy-1-ethylethyl)phenyl]propyl]thio]methyl]cyclopropaneacetic acid, monosodium salt. The empirical formula is C 35 H 35 ClNNaO 3 S, and its molecular weight is 608.18. Montelukast sodium is a hygroscopic, optically active, white to off-white powder. Montelukast sodium is freely soluble in ethanol, methanol, and water and practically insoluble in acetonitrile. Each 10-mg film-coated MONTAIR tablet contains 10.4 mg montelukast sodium, which is the molar equivalent to 10.0 mg of free acid, and the following inactive ingredients: microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, hydroxypropyl cellulose, and magnesium stearate. The film coating consists of: hydroxypropyl methylcellulose, hydroxypropyl cellulose, titanium dioxide, red ferric oxide, yellow ferric oxide, and carnauba wax. Each 4-mg and 5-mg chewable MONTAIR tablet for oral administration contains 4.2 and 5.2 mg montelukast sodium, respectively, which are the molar equivalents to 4.0 and 5.0 mg of free acid, respectively. Both chewable tablets contain the following inactive ingredients: mannitol, microcrystalline cellulose, hydroxypropyl cellulose, red ferric oxide, croscarmellose sodium, cherry flavor, aspartame, and magnesium stearate. CLINICAL PHARMACOLOGY Mechanism of Action The cysteinyl leukotrienes (LTC 4 , LTD 4 , LTE 4 ) are products of arachidonic acid metabolism and are released from various cells, including mast cells and eosinophils. These eicosanoids bind to cysteinyl leukotriene receptors (CysLT) found in the human airway. Cysteinyl leukotrienes and leukotriene receptor occupation have been correlated with the pathophysiology of asthma, including airway edema, smooth muscle contraction, and altered cellular activity associated with the inflammatory process, which contribute to the signs and symptoms of asthma. Montelukast is an orally active compound that binds with high affinity and selectivity to the CysLT 1 receptor (in preference to other pharmacologically important airway receptors, such as the prostanoid, cholinergic, or (beta)-adrenergic receptor). Montelukast inhibits physiologic actions of LTD 4 at the CysLT 1 receptor without any agonist activity. Pharmacokinetics Absorption Montelukast is rapidly absorbed following oral administration. After administration of the 10-mg film-coated tablet to fasted adults, the mean peak montelukast plasma concentration (C max ) is achieved in 3 to 4 hours (T max ). The mean oral bioavailability is 64%. The oral bioavailability and C max are not influenced by a standard meal in the morning. 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 safety and efficacy of MONTAIR were demonstrated in clinical trials in which the 10-mg and 5-mg formulations were administered in the evening without regard to the timing of food ingestion. The comparative pharmacokinetics of montelukast when administered as two 5-mg chewable tablets versus one 10-mg film-coated tablet have not been evaluated. Distribution Montelukast is more than 99% bound to plasma proteins. The steady-state volume of distribution of montelukast averages 8 to 11 liters. Studies in rats with radiolabeled 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 Montelukast is extensively metabolized. In studies with therapeutic doses, plasma concentrations of metabolites of montelukast are undetectable at steady state in adults and pediatric patients. In vitro studies using human liver microsomes indicate that cytochromes P450 3A4 and 2C9 are involved in the metabolism of montelukast. Clinical studies investigating the effect of known inhibitors of cytochromes P450 3A4 (e.g., ketoconazole, erythromycin) or 2C9 (e.g., fluconazole) on montelukast pharmacokinetics have not been conducted. Based on further in vitro results in human liver microsomes, therapeutic plasma concentrations of montelukast do not inhibit cytochromes P450 3A4, 2C9, 1A2, 2A6, 2C19, or 2D6 (see Drug Interactions ). Elimination The plasma clearance of montelukast averages 45 mL/min in healthy adults. Following an oral dose of radiolabeled montelukast, 86% of the radioactivity was recovered in 5-day fecal collections and <0.2% was recovered in urine. Coupled with estimates of montelukast oral bioavailability, this indicates that montelukast and its metabolites are excreted almost exclusively via the bile. In several studies, the mean plasma half-life of montelukast ranged from 2.7 to 5.5 hours in healthy young adults. The pharmacokinetics of montelukast are nearly linear for oral doses up to 50 mg. During once-daily dosing with 10-mg montelukast, there is little accumulation of the parent drug in plasma (~14%). Special Populations Gender The pharmacokinetics of montelukast are similar in males and females. Elderly: The pharmacokinetic profile and the oral bioavailability of a single 10-mg oral dose of montelukast are similar in elderly and younger adults. The plasma half-life of montelukast is slightly longer in the elderly. No dosage adjustment in the elderly is required. Race: Pharmacokinetic differences due to race have not been studied. Hepatic Insufficiency: Patients with mild-to-moderate hepatic insufficiency and clinical evidence of cirrhosis had evidence of decreased metabolism of montelukast resulting in 41% (90% Cl=7%, 85%) higher mean montelukast area under the plasma concentration curve (AUC) following a single 10-mg dose. The elimination of montelukast was slightly prolonged compared with that in healthy subjects (mean half-life, 7.4 hours). No dosage adjustment is required in patients with mild-to-moderate hepatic insufficiency. The pharmacokinetics of MONTAIR in patients with more severe hepatic impairment or with hepatitis have not been evaluated. Renal Insufficiency: Since montelukast and its metabolites are not excreted in the urine, the pharmacokinetics of montelukast were not evaluated in patients with renal insufficiency. No dosage adjustment is recommended in these patients. Adolescents and Pediatric Patients: The plasma concentration profile of montelukast following administration of the 10-mg film-coated tablet is similar in adolescents >/=15 years of age and young adults. The 10-mg film-coated tablet is recommended for use in patients >/=15 years of age. Pharmacokinetic studies show that the mean systemic exposure (in terms of AUC) of the 5-mg chewable tablet in pediatric patients 6 to 14 years of age is similar to that of the 10-mg film-coated tablet in adults. In a pharmacokinetic study in pediatric patients 2 to 5 years of age, the mean systemic exposure (AUC) of the 4-mg chewable tablet is also similar to that 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. Drug Interactions 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 1A2 substrate). did not change the pharmacokinetic profile of warfarin (a substrate of cytochromes P450 2A6 and 2C9) or influence the effect of a single 30-mg oral dose of warfarin on prothrombin time or the INR (International Normalized Ratio). did not change the pharmacokinetic profile or urinary excretion of immunoreactive digoxin. did not change the plasma concentration profile of terfenadine (a substrate of cytochrome P450 3A4) or fexofenadine, its carboxylated metabolite, and did not prolong the QTc interval following coadministration with terfenadine 60 mg twice daily. 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. did not cause any clinically significant change in plasma profiles of prednisone or prednisolone following administration of either oral prednisone or intravenous prednisolone. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for MONTAIR is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with MONTAIR. Pharmacodynamics Montelukast causes inhibition of airway cysteinyl leukotriene receptors as demonstrated by the ability to inhibit bronchoconstriction due to inhaled LTD 4 in asthmatics. Doses as low as 5 mg cause substantial blockage of LTD 4 -induced bronchoconstriction. In a placebo-controlled, crossover study (n=12), MONTAIR inhibited early- and late-phase bronchoconstriction due to antigen challenge by 75% and 57%, respectively. The effect of MONTAIR on eosinophils in the peripheral blood was examined in clinical trials in adults and pediatric asthmatic patients. MONTAIR decreased mean peripheral blood eosinophils approximately 13 to 15% from baseline compared with placebo over the double-blind treatment periods. The relationship between this observation and the clinical benefits noted in the clinical trials is not known (see CLINICAL PHARMACOLOGY , Clinical Studies ). Clinical Studies GENERAL There have been no clinical trials evaluating the relative efficacy of morning versus evening dosing. Although the pharmacokinetics of montelukast are similar whether dosed in the morning or the evening, efficacy was demonstrated in clinical trials in adults and pediatric patients in which montelukast was administered in the evening without regard to the time of food ingestion. ADOLESCENTS AND ADULTS 15 YEARS OF AGE AND OLDER Clinical trials in adolescents and adults 15 years of age and older demonstrated there is no additional clinical benefit to montelukast doses above 10 mg once daily. This was shown in two chronic asthma trials using doses up to 200 mg once daily and in one exercise challenge study using doses up to 50 mg, evaluated at the end of the once-daily dosing interval. The efficacy of MONTAIR for the chronic treatment of asthma in adolescents and adults 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 MONTAIR, 530 treated with placebo, and 251 treated with active control). The patients studied were mild and moderate, non-smoking asthmatics who required approximately 5 puffs of inhaled (beta)-agonist per day on an "as-needed" basis. The patients had a mean baseline percent of predicted forced expiratory volume in 1 second (FEV 1 ) of 66% (approximate range, 40 to 90%). The co-primary endpoints in these trials were FEV 1 and daytime asthma symptoms. Secondary endpoints included morning and evening peak expiratory flow rates (AM PEFR, PM PEFR), rescue (beta)-agonist requirements, nocturnal awakening due to asthma, and other asthma-related outcomes. In both studies after 12 weeks, a random subset of patients receiving MONTAIR 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, FEV 1 , expressed as mean percent change from baseline, are shown in FIGURE 1. The effect of MONTAIR on other primary and secondary endpoints is shown in TABLE 1 as combined analyses of the U.S. and Multinational trials. TABLE 1 Effect of MONTAIR on Primary and Secondary Endpoints in Placebo-controlled Trials (Combined Analyses - U.S. and Multinational Trials) MONTAIR Placebo Endpoint Baseline Mean Change from Baseline Baseline Mean Change from Baseline Daytime Asthma Symptoms (0 to 6 scale) 2.43 -0.45 * 2.45 -0.22 (beta)-agonist (puffs per day) 5.38 -1.56 * 5.55 -0.41 AM PEFR (L/min) 361.3 24.5 * 364.9 3.3 PM PEFR (L/min) 385.2 17.9 * 389.3 2.0 Nocturnal Awakenings (#/week) 5.37 -1.84 * 5.44 -0.79 * p<0.001, compared with placebo In adult patients, MONTAIR reduced "as-needed" (beta)-agonist use by 26.1% from baseline compared with 4.6% for placebo. In patients with nocturnal awakenings of at least 2 nights per week, MONTAIR reduced the nocturnal awakenings by 34% from baseline, compared with 15% for placebo (combined analysis). MONTAIR, compared with placebo, significantly improved other protocol-defined, asthma-related outcome measurements (see TABLE 2). TABLE 2 Effect of MONTAIR on Asthma-Related Outcome Measurements (Combined Analyses - U.S. and Multinational Trials) MONTAIR Placebo Asthma Attack * (% of patients) 11.6 # 18.4 Oral Corticosteroid Rescue (% of patients) 10.7 # 17.5 Discontinuation Due to Asthma (% of patients) 1.4 & 4.0 Asthma Exacerbations ** (% of days) 12.8 # 20.5 Asthma Control Days *** (% of days) 38.5 # 27.2 Physicians' Global Evaluation (score)  1.77 # 2.43 Patients' Global Evaluation (score)  1.60 # 2.15 # p<0.001, compared with placebo & p<0.01, compared with placebo * Asthma Attack defined as utilization of health-care resources such as an unscheduled visit to a doctor' office, emergency room, or hospital; or treatment with oral, intravenous, or intramuscular corticosteroid. ** Asthma Exacerbation defined by specific clinically important decreases in PEFR, increase in (beta)-agonist use, increases in day or nighttime symptoms, or the occurrence of an asthma attack. *** An Asthma Control Day defined as a day without any of the following: nocturnal awakening, use of more than 2 puffs of (beta)-agonist, or an asthma attack.  Physicians' evaluation of the patient' asthma, ranging from 0 to 6 ("very much better" through "very much worse," respectively).  Patients' evaluation of asthma, ranging from 0 to 6 ("very much better" through "very much worse," respectively). In one of these trials, a non-U.S. formulation of inhaled beclomethasone dipropionate dosed at 200 mcg (two puffs of 100 mcg ex-valve) twice daily with a spacer device was included as an active control. Over the 12-week treatment period, the mean percentage change in FEV 1 over baseline for MONTAIR and beclomethasone were 7.49% vs 13.3% (p<0.001) respectively, see FIGURE 2; and the change in daytime symptom scores was -0.49 vs -0.70 on a 0 to 6 scale (p<0.001) for MONTAIR and beclomethasone, respectively. Onset of Action and Maintenance of Benefits In each placebo-controlled trial in adults, the treatment effect of MONTAIR, measured by daily diary card parameters, including symptom scores, "as-needed" (beta)-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 MONTAIR in asthmatic patients after 12 weeks of continuous use did not cause rebound worsening of asthma. PEDIATRIC PATIENTS 6 TO 14 YEARS OF AGE The efficacy of MONTAIR 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 MONTAIR and 135 treated with placebo) using an inhaled (beta)-agonist on an "as-needed" basis. The patients had a mean baseline percent predicted FEV 1 of 72% (approximate range, 45 to 90%) and a mean daily inhaled (beta)-agonist requirement of 3.4 puffs of albuterol. Approximately 36% of the patients were on inhaled corticosteroids. Compared with placebo, treatment with one 5-mg MONTAIR chewable tablet daily, resulted in a significant improvement in mean morning FEV 1 percent change from baseline (8.7% in the group treated with MONTAIR 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 (beta)-agonist use (11.7% decrease from baseline in the group treated with MONTAIR 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 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. MONTAIR, one 5-mg chewable tablet daily at bedtime, significantly decreased the percent of days asthma exacerbations occurred (MONTAIR 20.6% vs placebo 25.7%, p/=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 MONTAIR. 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). MONTAIR should not be used as monotherapy for the treatment and management of exercise-induced bronchospasm. Patients who have exacerbations of asthma after exercise should continue to use their usual regimen of inhaled (beta)-agonists as prophylaxis and have available for rescue a short-acting inhaled (beta)-agonist (see PRECAUTIONS , General and Information for Patients ). INDICATIONS AND USAGE MONTAIR is indicated for the prophylaxis and chronic treatment of asthma in adults and pediatric patients 2 years of age and older. CONTRAINDICATIONS Hypersensitivity to any component of this product. PRECAUTIONS General MONTAIR 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 MONTAIR can be continued during acute exacerbations of asthma. While the dose of inhaled corticosteroid may be reduced gradually under medical supervision, MONTAIR should not be abruptly substituted for inhaled or oral corticosteroids. MONTAIR should not be used as monotherapy for the treatment and management of exercise-induced bronchospasm. Patients who have exacerbations of asthma after exercise should continue to use their usual regimen of inhaled (beta)-agonists as prophylaxis and have available for rescue a short-acting inhaled (beta)-agonist. Patients with known aspirin sensitivity should continue avoidance of aspirin or non-steroidal anti-inflammatory agents while taking MONTAIR. Although MONTAIR 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 PHARMACOLOGY , Clinical Studies ). Eosinophilic Conditions In rare cases, patients on therapy with MONTAIR 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 MONTAIR and these underlying conditions has not been established (see ADVERSE REACTIONS ). Information for Patients Patients should be advised to take MONTAIR 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 tablets of MONTAIR are not for the treatment of acute asthma attacks. They should have appropriate short-acting inhaled (beta)-agonist medication available to treat asthma exacerbations. Patients should be advised that, while using MONTAIR, 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 24-hour period are needed. Patients receiving MONTAIR should be instructed not to decrease the dose or stop taking any other antiasthma medications unless instructed by a physician. Patients who have exacerbations of asthma after exercise should be instructed to continue to use their usual regimen of inhaled (beta)-agonists as prophylaxis unless otherwise instructed by their physician. All patients should have available for rescue a short-acting inhaled (beta)-agonist. Patients with known aspirin sensitivity should be advised to continue avoidance of aspirin or non-steroidal anti-inflammatory agents while taking MONTAIR. Chewable Tablets Phenylketonurics: Phenylketonuric patients should be informed that the 4-mg and 5-mg chewable tablets contain phenylalanine (a component of aspartame), 0.674 and 0.842 mg per 4-mg and 5-mg chewable tablet, respectively. Drug Interactions MONTAIR has been administered with other therapies routinely used in the prophylaxis and chronic treatment of asthma with no apparent increase in adverse reactions. In drug-interaction studies, the recommended clinical dose of montelukast did not have clinically important effects on the pharmacokinetics of the following drugs: theophylline, prednisone, prednisolone, oral contraceptives (norethindrone 1 mg/ethinyl estradiol 35 mcg), terfenadine, digoxin, and warfarin. Although additional specific interaction studies were not performed, MONTAIR 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. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for MONTAIR is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with MONTAIR. Carcinogenesis, Mutagenesis, Impairment of Fertility No evidence of tumorigenicity was seen in either a 2-year carcinogenicity study in Sprague-Dawley rats at oral (gavage) doses up to 200 mg/kg/day (estimated exposure was approximately 120 times the area under the plasma concentration versus time curve (AUC) for adults and children at the maximum recommended daily oral dose) or in a 92-week carcinogenicity study in mice at oral (gavage) doses up to 100 mg/kg/day (estimated exposure was approximately 45 times the AUC for adults and children at the maximum recommended daily oral dose. Montelukast 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, 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). 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). Pregnancy, Teratogenic Effects Pregnancy Category B: No teratogenicity was observed in rats at oral doses up to 400 mg/kg/day (estimated exposure was approximately 100 times the AUC for adults at the maximum recommended daily oral dose) and in rabbits at oral doses up to 300 mg/kg/day (estimated exposure was approximately 110 times the AUC for adults at the maximum recommended daily oral dose). Montelukast crosses the placenta following oral dosing in rats and rabbits. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, MONTAIR should be used during pregnancy only if clearly needed. Merck & Co., Inc. maintains a registry to monitor the pregnancy outcomes of women exposed to MONTAIR while pregnant. Healthcare providers are encouraged to report any prenatal exposure to MONTAIR by calling the Pregnancy Registry at (800) 986-8999. Nursing Mothers Studies in rats have shown that montelukast is excreted in milk. It is not known if montelukast is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when MONTAIR is given to a nursing mother. Pediatric Use Safety and efficacy of MONTAIR have been established in adequate and well-controlled studies in pediatric patients 6 to 14 years of age. Safety and efficacy profiles in this age group are similar to those seen in adults. (See Clinical Studies and ADVERSE REACTIONS .) The safety of MONTAIR 4-mg chewable tablets in pediatric patients 2 to 5 years of age has been demonstrated in an interim analysis of 314 pediatric patients in a 12-week double-blind, placebo-controlled study in approximately 650 patients (see ADVERSE REACTIONS ). Efficacy of MONTAIR in this age group is extrapolated from the demonstrated efficacy in adolescent and adult patients 15 years of age and older and pediatric patients 6 to 14 years of age with asthma based on similar mean systemic exposure (AUC), and that the disease course, pathophysiology and the drug's effect are substantially similar among these populations. The safety and effectiveness in pediatric patients below the age of 2 years have not been established. Long-term trials evaluating the effect of chronic administration of MONTAIR on linear growth in pediatric patients have not been conducted. Geriatric Use Of the total number of subjects in clinical studies of montelukast, 3.5% were 65 years of age and over and 0.4% were 75 years of age and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. ADVERSE REACTIONS Adolescents and Adults 15 Years of Age and Older MONTAIR has been evaluated for safety in approximately 2600 adolescent and adult patients 15 years of age and older in clinical trials. In placebo-controlled clinical trials, the following adverse experiences reported with MONTAIR occurred in greater than or equal to 1% of patients and at an incidence greater than that in patients treated with placebo, regardless of causality assessment: Adverse Experiences Occurring in >/=1% of Patients with an Incidence Greater than that in Patients Treated with Placebo, Regardless of Causality Assessment MONTAIR 10 mg/day (%) Placebo(%) (n=1955) (n=1180) 1 Body As A Whole Asthenia/fatigue 1.8 1.2 Fever 1.5 0.9 Pain, abdominal 2.9 2.5 Trauma 1.0 0.8 Digestive System Disorders Dyspepsia 2.1 1.1 Gastroenteritis, infectious 1.5 0.5 Pain, dental 1.7 1.0 Nervous System/Psychiatric Dizziness 1.9 1.4 Headache 18.4 18.1 Respiratory System Disorders Congestion, nasal 1.6 1.3 Cough 2.7 2.4 Influenza 4.2 3.9 Skin/Skin Appendages Disorder Rash 1.6 1.2 Laboratory Adverse Experiences * ALT increased 2.1 2.0 AST increased 1.6 1.2 Pyuria 1.0 0.9 ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- *Number of patients tested (MONTAIR and placebo, respectively): ALT and AST, 1935, 1170; pyuria, 1924, 1159. The frequency of less common adverse events was comparable between MONTAIR and placebo. Cumulatively, 569 patients were treated with MONTAIR 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 MONTAIR has also been evaluated for safety in approximately 320 pediatric patients 6 to 14 years of age. Cumulatively, 169 pediatric patients were treated with MONTAIR for at least 6 months, and 121 for one year or longer in clinical trials. The safety profile of MONTAIR versus placebo in the double-blind, 8-week, pediatric efficacy trial was generally similar to the adult safety profile with the exception of the adverse events listed below. In pediatric patients 6 to 14 years of age receiving MONTAIR, the following events occurred with a frequency >/=2% and more frequently than in pediatric patients who received placebo, regardless of causality assessment: diarrhea, laryngitis, pharyngitis, nausea, otitis, sinusitis, and viral infection. The frequency of less common adverse events was comparable between MONTAIR and placebo. With prolonged treatment, the adverse experience profile did not significantly change. Pediatric Patients 2 to 5 Years of Age Safety data for MONTAIR in pediatric patients 2 to 5 years of age are available from an interim analysis of 314 pediatric patients from a 12-week, double-blind, placebo-controlled clinical study in approximately 650 patients. The safety profile of MONTAIR in this interim analysis of patients who received MONTAIR for at least 6 weeks was generally similar to the safety profile in pediatric patients 6 to 14 years of age. In pediatric patients 2 to 5 years of age receiving MONTAIR, the following events occurred with a frequency >/=2% and more frequently than in pediatric patients who received placebo, regardless of causality assessment: rhinorrhea, otitis, ear pain, bronchitis, leg pain, thirst, sneezing, rash and urticaria. Post-Marketing Experience The following additional adverse reactions have been reported in post-marketing use: hypersensitivity reactions (including anaphylaxis, angioedema, pruritus, urticaria, and very rarely, hepatic eosinophilic infiltration), dream abnormalities, drowsiness, irritability, restlessness, insomnia, nausea, vomiting, dyspepsia and diarrhea. In rare cases, patients on therapy with MONTAIR 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 MONTAIR and these underlying conditions has not been established (see PRECAUTIONS , Eosinophilic Conditions ). OVERDOSAGE No mortality occurred following single oral doses of montelukast up to 5000 mg/kg in mice (estimated exposure was approximately 340 times the AUC for adults and children at the maximum recommended daily oral dose) and rats (estimated exposure was approximately 230 times the AUC for adults and children at the maximum recommended daily oral dose). No specific information is available on the treatment of overdosage with MONTAIR. In chronic asthma studies, montelukast has been administered at doses up to 200 mg/day to 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 pediatric patients in post-marketing experience and clinical studies of up to at least 150 mg/day with MONTAIR. The clinical and laboratory findings observed were consistent with the safety profile in adults and older pediatric patients. There were no adverse experiences reported in the majority of overdosage reports. The most frequent adverse experiences observed were thirst, somnolence, mydriasis, hyperkinesia, and abdominal pain. It is not known whether montelukast is removed by peritoneal dialysis or hemodialysis. DOSAGE AND ADMINISTRATION General Information: Adolescents and Adults 15 Years of Age and Older The dosage for adolescents and adults 15 years of age and older is one 10-mg tablet daily to be taken in the evening. Pediatric Patients 6 to 14 Years of Age The dosage for pediatric patients 6 to 14 years of age is one 5-mg chewable tablet daily to be taken in the evening. No dosage adjustment within this age group is necessary. Pediatric Patients 2 to 5 Years of Age The dosage for pediatric patients 2 to 5 years of age is one 4-mg chewable tablet daily to be taken in the evening. Safety and effectiveness in pediatric patients younger than 2 years of age have not been established. The safety and efficacy of MONTAIR was demonstrated in clinical trials where it was administered in the evening without regard to the time of food ingestion. There have been no clinical trials evaluating the relative efficacy of morning versus evening dosing. ANTI-LEUKOTRIENES AND THEIR SCOPE IN ASTHMA THERAPY Q l Why do we need anti-leukotrienes? Ans Anti-leukotrienes may benefit in patients who-suffer from poorly controlled asthma despite being on inhaled steroids. They may also prove to be useful in patients who experience exercise-induced bronchoconstriction since, the plasma levels of leukotrienes go up during exercise. Q 2 What are the different anti-leukotrienes available today? Ans The anti-leukotrienes available today are: l) Leukotriene synthesis inhibitors These drugs inhibit the enzyme 5-lipooxygenase, and thus they stop the formation of leukotrienes. E.g., Zileuton 2) Leukotriene receptor antagonists (LTRAs) These drugs block the leukotriene receptors Cys LTl and thus do not allow the leukotrienes to act at all. E.g., Montelukast, Zafirlukast Q3 How many types of leukotriene receptors are there? Ans There are two types of leukotriene receptors-,  Cys LTl - They are present on the bronchial smooth muscle  Cys LTl - They are present on the bronchial smooth muscle and are responsible for the leukotriene-induced bronchoconstriction.  Cys LT2 - They are present on the smooth muscle of the pulmonary vessels, and have a role in pulmonary vasoconstriction. Q4 .What is the role of anti-leukotrienes in asthma therapy today? Ans Inhaled corticosteroids and beta-agonists are considered currently as the most effective treatments for persistent mild-to-moderate asthma. However, there is room for improvement in certain areas such as drug tolerability, mode of administration, and patient compliance with therapy. Leukotriene antagonists may improve upon current therapy in any one or more of these areas. Q5 What advantage can the anti-leukotrienes provide to existing asthma therapy? Ans Anti-leukotrienes can help existing asthma therapy in the following manner; * Their oral administration may contribute to improved patient compliance with treatment. -  Their use may also be associated with a reduced need for beta-agonist therapy, as they have been shown to improve pulmonary function, in addition to reducing the severity of asthma-associated symptoms.  These agents may be used as adjunctive therapy for patients with sub optimally controlled symptoms who are taking inhaled corticosteroids. This also allows for improved lung function at reduced dosage of corticosteroids.