ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. Use of levocetirizine has been associated with somnolence, fatigue, asthenia, and urinary retention [see Warnings and Precautions (5)]. The most common adverse reactions (rate >=2% and placebo) were somnolence, nasopharyngitis, fatigue, dry mouth, and pharyngitis in subjects 12 years of age and older, and pyrexia, somnolence, cough, and epistaxis in children to 12 years of age (6.1). To report SUSPECTED ADVERSE REACTIONS, contact CARACO Pharmaceutical Laboratories Ltd. at 1-800-818-4555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience. The safety data described below reflect exposure to levocetirizine in 12 controlled clinical trials of week to months duration. The short-term (exposure up to weeks) safety data for adults and adolescents are based upon eight clinical trials in which 1896 patients (825 males and 1071 females aged 12 years and older) were treated with levocetirizine 2.5 mg, mg, or 10 mg once daily in the evening. The short-term safety data from pediatric patients are based upon two clinical trials in which 243 children (162 males and 81 females to 12 years of age) were treated with levocetirizine mg once daily for to weeks. The long-term (exposure of or months) safety data in adults and adolescents are based upon two clinical trials in which 428 patients (190 males and 238 females) were exposed to treatment with levocetirizine mg once daily. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trial of another drug and may not reflect the rates observed in practice. Adults and Adolescents 12 years of Age and Older In studies up to weeks in duration, the mean age of the adult and adolescent patients was 32 years, 44% of the patients were men and 56% were women, and the large majority (more than 90%) was Caucasian. In these trials 43% and 42% of the subjects in the levocetirizine 2.5 mg and mg groups, respectively, had at least one adverse event compared to 43% in the placebo group. In placebo-controlled trials of to weeks in duration, the most common adverse reactions were somnolence, nasopharyngitis, fatigue, dry mouth, and pharyngitis, and most were mild to moderate in intensity. Somnolence with levocetirizine showed dose ordering between tested doses of 2.5 mg, mg and 10 mg and was the most common adverse reaction leading to discontinuation (0.5%). Table lists adverse reactions that were reported in greater than or equal to 2% of subjects aged 12 years and older exposed to levocetirizine 2.5 mg or mg in eight placebo-controlled clinical trials and that were more common with levocetirizine than placebo.Table Adverse Reactions Reported in >= 2%Rounded to the closest unit percentage of Subjects Aged 12 Years and Older Exposed to Levocetirizine 2.5 mg or mg Once Daily in Placebo-Controlled Clinical Trials to Weeks in Duration Adverse ReactionsLevocetirizine 2.5 mg(n 421)Levocetirizine mg(n 1070)Placebo(n 912) Somnolence 22 (5%) 61 (6%) 16 (2%) Nasopharyngitis 25 (6%) 40 (4%) 28 (3%) Fatigue (1%) 46 (4%) 20 (2%) Dry Mouth 12 (3%) 26 (2%) 11 (1%) Pharyngitis 10 (2%) 12 (1%) (1%) Additional adverse reactions of medical significance observed at higher incidence than in placebo in adults and adolescents aged 12 years and older exposed to levocetirizine are syncope (0.2%) and weight increased (0.5%). Pediatric Patients to 12 Years of Age total of 243 pediatric patients to 12 years of age received levocetirizine mg once daily in two short-term placebo controlled double-blind trials. The mean age of the patients was 9.8 years, 79 (32%) were to years of age, and 50% were Caucasian. Table lists adverse reactions that were reported in greater than or equal to 2% of subjects aged to 12 years exposed to levocetirizine mg in placebo-controlled clinical trials and that were more common with levocetirizine than placebo.Table Adverse Reactions Reported in >=2%Rounded to the closest unit percentage of Subjects Aged to 12 Years Exposed to Levocetirizine mg Once Daily in Placebo-Controlled Clinical Trials and Weeks in Duration Adverse ReactionsLevocetirizine mg(n 243)Placebo(n 240) Pyrexia 10 (4%) (2%) Cough (3%) (<1%) Somnolence (3%) (<1%) Epistaxis (2%) (<1%) Clinical trial information in pediatric patients (age months to years) is approved for UCB Inc.s levocetirizine dihydrochloride drug product labeling. However, due to UCB Inc.s marketing exclusivity rights; this drug product is not labeled for such use in those pediatric patients.Long-Term Clinical Trials ExperienceIn two controlled clinical trials, 428 patients (190 males and 238 females) aged 12 years and older were treated with levocetirizine mg once daily for or months. The patient characteristics and the safety profile were similar to that seen in the short-term studies. Ten (2.3%) patients treated with levocetirizine discontinued because of somnolence, fatigue or asthenia compared to (<1%) in the placebo group.There are no long term clinical trials in children below 12 years of age with chronic idiopathic urticaria.Laboratory Test AbnormalitiesElevations of blood bilirubin and transaminases were reported in <1% of patients in the clinical trials. The elevations were transient and did not lead to discontinuation in any patient.. 6.2 Postmarketing Experience. In addition to the adverse reactions reported during clinical trials and listed above, adverse events have also been identified during post-approval use of levocetirizine. Because these events are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure. Adverse events of hypersensitivity and anaphylaxis, increased appetite, angioedema, fixed drug eruption, pruritus, rash, and urticaria, convulsion, paraesthesia, dizziness, tremor, dysgeusia, vertigo, aggression and agitation, hallucinations, depression, insomnia, suicidal ideation, visual disturbances, blurred vision, palpitations, tachycardia, dyspnea, nausea, vomiting, hepatitis, dysuria, urinary retention, myalgia, and edema have been reported. Besides these events reported under treatment with levocetirizine, other potentially severe adverse events have been reported from the postmarketing experience with cetirizine. Since levocetirizine is the principal pharmacologically active component of cetirizine, one should take into account the fact that the following adverse events could also potentially occur under treatment with levocetirizine: orofacial dyskinesia, severe hypotension, cholestasis, glomerulonephritis, and still birth.

ANIMAL PHARMACOLOGY & OR TOXICOLOGY SECTION.

13.2 Animal Toxicology. Reproductive Toxicology Studies In rats and rabbits, levocetirizine was not teratogenic at oral doses up to 200 and 120 mg/kg, respectively, (approximately 320 and 390, respectively, times the maximum recommended daily oral dose in adults on mg/m2 basis). In mice, cetirizine 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 mg/m2 basis).

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. No carcinogenicity studies have been performed with levocetirizine. However, evaluation of cetirizine carcinogenicity studies are relevant for determination of the carcinogenic potential of levocetirizine. In 2-year carcinogenicity study, in rats, cetirizine was not carcinogenic at dietary doses up to 20 mg/kg (approximately 15 times the maximum recommended daily oral dose in adults, approximately 10 times the maximum recommended daily oral dose in children to 11 years of age and approximately 15 times the maximum recommended daily oral dose in children months to years of age on mg/m2 basis). In 2-year carcinogenicity study in mice, cetirizine caused an increased incidence of benign hepatic tumors in males at dietary dose of 16 mg/kg (approximately times the maximum recommended daily oral dose in adults, approximately times the maximum recommended daily oral dose in children to 11 years of age, and approximately times the maximum recommended daily oral dose in children months to years of age on mg/m2 basis). No increased incidence of benign tumors was observed at dietary dose of mg/kg (approximately times the maximum recommended daily oral dose in adults, equivalent to the maximum recommended daily oral dose in children to 11 years of age and approximately times the maximum recommended daily oral dose in children months to years of age on mg/m2 basis). The clinical significance of these findings during long-term use of levocetirizine 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 mice. In fertility and general reproductive performance study in mice, cetirizine did not impair fertility at an oral dose of 64 mg/kg (approximately 25 times the recommended daily oral dose in adults on mg/m2 basis).

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Levocetirizine, the active enantiomer of cetirizine, is an anti-histamine; its principal effects are mediated via selective inhibition of H1 receptors. The antihistaminic activity of levocetirizine has been documented in variety of animal and human models. In vitro binding studies revealed that levocetirizine has an affinity for the human H1-receptor 2-fold higher than that of cetirizine (Ki 3 nmol/L vs. nmol/L, respectively). The clinical relevance of this finding is unknown.. 12.2 Pharmacodynamics. Studies in adult healthy subjects showed that levocetirizine at doses of 2.5 mg and mg inhibited the skin wheal and flare caused by the intradermal injection of histamine. In contrast, dextrocetirizine exhibited no clear change in the inhibition of the wheal and flare reaction. Levocetirizine at dose of mg inhibited the wheal and flare caused by intradermal injection of histamine in 14 pediatric subjects (aged to 11 years) and the activity persisted for at least 24 hours. The clinical relevance of histamine wheal skin testing is unknown. QT/QTc study using single dose of 30 mg of levocetirizine did not demonstrate an effect on the QTc interval. While single dose of levocetirizine had no effect, the effects of levocetirizine may not be at steady state following single dose. The effect of levocetirizine on the QTc interval following multiple dose administration is unknown. Levocetirizine is not expected to have QT/QTc effects because of the results of QTc studies with cetirizine and the long postmarketing history of cetirizine without reports of QT prolongation.. 12.3 Pharmacokinetics. Levocetirizine exhibited linear pharmacokinetics over the therapeutic dose range in adult healthy subjects. Absorption Levocetirizine is rapidly and extensively absorbed following oral administration. In adults, peak plasma concentrations are achieved 0.9 hour after administration of the oral tablet. The accumulation ratio following daily oral administration is 1.12 with steady state achieved after days. Peak concentrations are typically 270 ng/mL and 308 ng/mL following single and repeated mg once daily dose, respectively. Food had no effect on the extent of exposure (AUC) of the levocetirizine tablet, but Tmax was delayed by about 1.25 hours and Cmax was decreased by about 36% after administration with high fat meal; therefore, levocetirizine can be administered with or without food.A dose of mg (10 mL) of levocetirizine dihydrochloride oral solution is bioequivalent to 5 mg dose of levocetirizine dihydrochloride tablets. Following oral administration of 5 mg dose of levocetirizine dihydrochloride oral solution to healthy adult subjects, the mean peak plasma concentrations were achieved approximately 0.5 hour post-dose. Distribution The mean plasma protein binding of levocetirizine in vitro ranged from 91 to 92%, independent of concentration in the range of 90 to 5000 ng/mL, which includes the therapeutic plasma levels observed. Following oral dosing, the average apparent volume of distribution is approximately 0.4 L/kg, representative of distribution in total body water. Metabolism The extent of metabolism of levocetirizine in humans is less than 14% of the dose and therefore differences resulting from genetic polymorphism or concomitant intake of hepatic drug metabolizing enzyme inhibitors are expected to be negligible. Metabolic pathways include aromatic oxidation, N- -and O-dealkylation, and taurine conjugation. Dealkylation pathways are primarily mediated by CYP 3A4 while aromatic oxidation involves multiple and/or unidentified CYP isoforms. Elimination The plasma half-life in adult healthy subjects was about to hours after administration of oral tablets and oral solution, and the mean oral total body clearance for levocetirizine was approximately 0.63 mL/kg/min. The major route of excretion of levocetirizine and its metabolites is via urine, accounting for mean of 85.4% of the dose. Excretion via feces accounts for only 12.9% of the dose. Levocetirizine is excreted both by glomerular filtration and active tubular secretion. Renal clearance of levocetirizine correlates with that of creatinine clearance. In patients with renal impairment the clearance of levocetirizine is reduced [see Dosage and Administration (2.3)]. Drug Interaction Studies In vitro data on metabolite interaction indicate that levocetirizine is unlikely to produce, or be subject to metabolic interactions. Levocetirizine at concentrations well above Cmax level achieved within the therapeutic dose ranges is not an inhibitor of CYP isoenzymes 1A2, 2C9, 2C19, 2A1, 2D6, 2E1, and 3A4, and is not an inducer of UGT1A or CYP isoenzymes 1A2, 2C9 and 3A4. No formal in vivo drug interaction studies have been performed with levocetirizine. Studies have been performed with the racemic cetirizine [see Drug Interactions (7)]. Pediatric Patients Data from pediatric pharmacokinetic study with oral administration of single dose of mg levocetirizine in 14 children age to 11 years with body weight ranging between 20 and 40 kg show that Cmax and AUC values are about 2-fold greater than that reported in healthy adult subjects in cross-study comparison. The mean Cmax was 450 ng/mL, occurring at mean time of 1.2 hours, weight-normalized, total body clearance was 30% greater, and the elimination half-life 24% shorter in this pediatric population than in adults. Dedicated pharmacokinetic studies have not been conducted in pediatric patients younger than years of age. Pharmacokinetic information in pediatric patients (age to years) is approved for UCB Inc.s levocetirizine dihydrochloride drug product labeling. However, due to UCB Inc.s marketing exclusivity rights; this drug product is not labeled for such use in those pediatric patients. Geriatric Patients Limited pharmacokinetic data are available in elderly subjects. Following once daily repeat oral administration of 30 mg levocetirizine for days in elderly subjects (65 to 74 years of age), the total body clearance was approximately 33% lower compared to that in younger adults. The disposition of racemic cetirizine has been shown to be dependent on renal function rather than on age. This finding would also be applicable for levocetirizine, as levocetirizine and cetirizine are both predominantly excreted in urine. Therefore, the levocetirizine dose should be adjusted in accordance with renal function in elderly patients [see Dosage and Administration (2)]. Gender Pharmacokinetic results for 77 patients (40 men, 37 women) were evaluated for potential effect of gender. The half-life was slightly shorter in women (7.08 +- 1.72 hr) than in men (8.62 +- 1.84 hr); however, the body weight-adjusted oral clearance in women (0.67 +- 0.16 mL/min/kg) appears to be comparable to that in men (0.59 +- 0.12 mL/min/kg). The same daily doses and dosing intervals are applicable for men and women with normal renal function. Race The effect of race on levocetirizine has not been studied. As levocetirizine is primarily renally excreted, and there are no important racial differences in creatinine clearance, pharmacokinetic characteristics of levocetirizine are not expected to be different across races. No race-related differences in the kinetics of racemic cetirizine have been observed. Renal Impairment Levocetirizine exposure (AUC) exhibited 1.8-, 3.2-, 4.3-, and 5.7-fold increase in mild, moderate, severe, renal impaired, and end-stage renal disease patients, respectively, compared to healthy subjects. The corresponding increases of half-life estimates were 1.4-, 2-, 2.9-, and 4-fold, respectively. The total body clearance of levocetirizine after oral dosing was correlated to the creatinine clearance and was progressively reduced based on severity of renal impairment. Therefore, it is recommended to adjust the dose and dosing intervals of levocetirizine based on creatinine clearance in patients with mild, moderate, or severe renal impairment. In end-stage renal disease patients (CLCR 10 mL/min) levocetirizine is contraindicated. The amount of levocetirizine removed during standard 4-hour hemodialysis procedure was <10%. The dosage of levocetirizine should be reduced in patients with mild renal impairment. Both the dosage and frequency of administration should be reduced in patients with moderate or severe renal impairment [see Dosage and Administration (2.4)]. Hepatic Impairment Levocetirizine has not been studied in patients with hepatic impairment. The non-renal clearance (indicative of hepatic contribution) was found to constitute about 28% of the total body clearance in healthy adult subjects after oral administration. As levocetirizine is mainly excreted unchanged by the kidney, it is unlikely that the clearance of levocetirizine is significantly decreased in patients with solely hepatic impairment [see Dosage and Administration (2)].

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.2 Chronic Idiopathic Urticaria. Adult Patients 18 Years of Age and OlderThe efficacy of levocetirizine for the treatment of the uncomplicated skin manifestations of chronic idiopathic urticaria was evaluated in two multi-center, randomized, placebo-controlled, double-blind clinical trials of weeks duration in adult patients 18 to 85 years of age with chronic idiopathic urticaria. The two trials included one 4-week dose-ranging trial and one 4-week single-dose level efficacy trial. These trials included 423 patients (139 males and 284 females). Most patients (>90%) were Caucasian and the mean age was 41. Of these patients, 146 received levocetirizine mg once daily in the evening. Efficacy was assessed based on patient recording of pruritus severity on severity score of to (0 none to = severe). The primary efficacy endpoint was the mean reflective pruritus severity score over the first week and over the entire treatment period. Additional efficacy variables were the instantaneous pruritus severity score, the number and size of wheals, and duration of pruritus.The dose-ranging trial was conducted to evaluate the efficacy of levocetirizine 2.5 mg, mg, and 10 mg once daily in the evening. In this trial, each of the three doses of levocetirizine demonstrated greater decrease in the reflective pruritus severity score than placebo and the difference was statistically significant for all three doses (see Table 3).The single dose level trial evaluated the efficacy of levocetirizine mg once daily in the evening compared to placebo in patients with chronic idiopathic urticaria over 4-week treatment period. Levocetirizine mg demonstrated greater decrease from baseline in the reflective pruritus severity score than placebo and the difference from placebo was statistically significant.Duration of pruritus, number and size of wheals, and instantaneous pruritus severity score also showed significant improvement over placebo. The significant improvement in the instantaneous pruritus severity score over placebo confirmed end of dosing interval efficacy (see Table 3).Table Mean Reflective Pruritus Severity Score in Chronic Idiopathic Urticaria Trials TreatmentNBaselineOn Treatment Adjusted MeanDifference from PlaceboEstimate95% CIp-value Dose-Ranging Trial Reflective pruritus severity score Levocetirizine 2.5 mg 69 2.08 1.02 0.82 (0.58, 1.06) <0.001 Levocetirizine mg 62 2.07 0.92 0.91 (0.66, 1.16) <0.001 Levocetirizine 10 mg 55 2.04 0.73 1.11 (0.85, 1.37) <0.001 Placebo 60 2.25 1.84 Chronic Idiopathic Urticaria Trial Reflective pruritus severity score Levocetirizine mg 80 2.07 0.94 0.62 (0.38, 0.86) <0.001 Placebo 82 2.06 1.56 Pediatric PatientsThere are no clinical efficacy trials in pediatric patients with chronic idiopathic urticaria [see Use in Specific Populations (8.4)].

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. The use of levocetirizine dihydrochloride tablet is contraindicated in:. Patients with known hypersensitivity to levocetirizine or any of the ingredients of levocetirizine dihydrochloride tablet or to cetirizine (4) Patients with end-stage renal disease at less than 10 mL/min creatinine clearance or patients undergoing hemodialysis (4) Children months to 11 years of age with renal impairment (4). Patients with known hypersensitivity to levocetirizine or any of the ingredients of levocetirizine dihydrochloride tablet or to cetirizine (4) Patients with end-stage renal disease at less than 10 mL/min creatinine clearance or patients undergoing hemodialysis (4) Children months to 11 years of age with renal impairment (4). 4.1 Patients with known hypersensitivity. Patients with known hypersensitivity to levocetirizine or any of the ingredients of levocetirizine dihydrochloride tablet, or to cetirizine. Observed reactions range from urticaria to anaphylaxis [see Adverse Reactions (6.2)]. 4.2 Patients with end-stage renal disease. Patients with end-stage renal disease (CLCR 10 mL/min) and patients undergoing hemodialysis.. 4.3 Pediatric patients with impaired renal function. Children months to 11 years of age with impaired renal function.

DESCRIPTION SECTION.

11 DESCRIPTION. Levocetirizine dihydrochloride, the active component of levocetirizine dihydrochloride tablets, is an orally active H1-receptor antagonist. The chemical name is (R)-[2-[4-[(4-chlorophenyl) phenylmethyl]-1-piperazinyl] ethoxy] acetic acid dihydrochloride. Levocetirizine dihydrochloride is the enantiomer of cetirizine hydrochloride, racemic compound with antihistaminic properties. The molecular formula of levocetirizine dihydrochloride is C21H25ClN2O3o2HCl. The molecular weight is 461.82 and the chemical structure is shown below:Levocetirizine dihydrochloride is white, crystalline powder and is water soluble. Levocetirizine dihydrochloride mg tablets are formulated as immediate-release, white, film-coated, oval-shaped scored tablets for oral administration. The tablets are debossed with on one side and breakline on other side. Inactive ingredients are: anhydrous lactose, microcrystalline cellulose, colloidal silicon dioxide, and magnesium stearate. The film coating contains hypromellose, polyethylene glycol, polysorbate 80, and titanium dioxide.. chemical-structure.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Levocetirizine dihydrochloride tablets are available as mg breakable (scored) tablets, allowing for the administration of 2.5 mg, if needed. Levocetirizine dihydrochloride tablets can be taken without regard to food consumption.. Adults and children 12 years of age and older: mg once daily in the evening (2.1) Children to 11 years of age: 2.5 mg once daily in the evening (2.2) Renal Impairment Adjust the dose in patients 12 years of age and older with decreased renal function (2.4, 12.3). Adults and children 12 years of age and older: mg once daily in the evening (2.1) Children to 11 years of age: 2.5 mg once daily in the evening (2.2) Renal Impairment Adjust the dose in patients 12 years of age and older with decreased renal function (2.4, 12.3). 2.1 Adults and Children 12 Years of Age and Older. The recommended dose of levocetirizine dihydrochloride tablet is mg (1 tablet) once daily in the evening. Some patients may be adequately controlled by 2.5 mg (1/2 tablet) once daily in the evening.. 2.2 Children to 11 Years of Age. The recommended dose of levocetirizine dihydrochloride tablet is 2.5 mg (1/2 tablet) once daily in the evening. The 2.5 mg dose should not be exceeded because the systemic exposure with mg is approximately twice that of adults [see Clinical Pharmacology (12.3)]. 2.3 Children months to Years of Age. Pediatric use information in pediatric patients (age months to years) is approved for UCB Inc.s levocetirizine dihydrochloride drug product labeling. However, due to UCB Inc.s marketing exclusivity rights; this drug product is not labeled for such use in those pediatric patients.. 2.4 Dose Adjustment for Renal and Hepatic Impairment. In adults and children 12 years of age and older with:Mild renal impairment (creatinine clearance [CLCR] 50 to 80 mL/min): dose of 2.5 mg once daily is recommended;Moderate renal impairment (CLCR 30 to 50 mL/min): dose of 2.5 mg once every other day is recommended;Severe renal impairment (CLCR 10 to 30 mL/min): dose of 2.5 mg twice weekly (administered once every to days) is recommended;End-stage renal disease patients (CLCR 10 mL/min) and patients undergoing hemodialysis should not receive levocetirizine dihydrochloride tablets.No dose adjustment is needed in patients with solely hepatic impairment. In patients with both hepatic impairment and renal impairment, adjustment of the dose is recommended.. Mild renal impairment (creatinine clearance [CLCR] 50 to 80 mL/min): dose of 2.5 mg once daily is recommended;. Moderate renal impairment (CLCR 30 to 50 mL/min): dose of 2.5 mg once every other day is recommended;. Severe renal impairment (CLCR 10 to 30 mL/min): dose of 2.5 mg twice weekly (administered once every to days) is recommended;. End-stage renal disease patients (CLCR 10 mL/min) and patients undergoing hemodialysis should not receive levocetirizine dihydrochloride tablets.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. Levocetirizine dihydrochloride tablets are white, film-coated, oval-shaped tablets debossed with on one side and breakline on other side and contain mg levocetirizine dihydrochloride.. Immediate-release breakable (scored) tablets, mg (3). Immediate-release breakable (scored) tablets, mg (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. In vitro data indicate that levocetirizine is unlikely to produce pharmacokinetic interactions through inhibition or induction of liver drug-metabolizing enzymes. No in vivo drug-drug interaction studies have been performed with levocetirizine. Drug interaction studies have been performed with racemic cetirizine.. 7.1 Antipyrine, Azithromycin, Cimetidine, Erythromycin, Ketoconazole, Theophylline, and Pseudoephedrine. Pharmacokinetic interaction studies performed with racemic cetirizine demonstrated that cetirizine did not interact with antipyrine, pseudoephedrine, erythromycin, azithromycin, ketoconazole, and cimetidine. There was small decrease (~16%) in the clearance of cetirizine caused by 400 mg dose of theophylline. It is possible that higher theophylline doses could have greater effect.. 7.2 Ritonavir. Ritonavir increased the plasma AUC of cetirizine by about 42% accompanied by an increase in half-life (53%) and decrease in clearance (29%) of cetirizine. The disposition of ritonavir was not altered by concomitant cetirizine administration.

GERIATRIC USE SECTION.

8.5 Geriatric Use. Clinical studies of levocetirizine for each approved indication did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently than younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. Levocetirizine dihydrochloride tablets are white, film-coated, oval-shaped tablets debossed with on one side and breakline on other side and contain mg levocetirizine dihydrochloride. They are supplied in HDPE bottles as follows: Bottles of 30s ...............NDC 33261-0947-30Storage:Store at 20 to 25C (68 to 77F); excursions permitted between 15 and 30C (59 and 86F) [see USP Controlled Room Temperature].

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. Levocetirizine dihydrochloride tablet is histamine H1-receptor antagonist indicated for:The treatment of the uncomplicated skin manifestations of chronic idiopathic urticaria (1.3). The treatment of the uncomplicated skin manifestations of chronic idiopathic urticaria (1.3). 1.3 Chronic Idiopathic Urticaria. Levocetirizine dihydrochloride tablets are indicated for the treatment of the uncomplicated skin manifestations of chronic idiopathic urticaria in adults and children years of age and older. Pediatric use information in pediatric patients (age months to years) is approved for UCB Inc.s levocetirizine dihydrochloride drug product labeling. However, due to UCB Inc.s marketing exclusivity rights; this drug product is not labeled for such use in those pediatric patients.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. 17.1 Somnolence. Caution patients against engaging in hazardous occupations requiring complete mental alertness, and motor coordination such as operating machinery or driving motor vehicle after ingestion of levocetirizine dihydrochloride tablets.. 17.2 Concomitant Use of Alcohol and other Central Nervous System Depressants. Instruct patients to avoid concurrent use of levocetirizine dihydrochloride tablets with alcohol or other central nervous system depressants because additional reduction in mental alertness may occur.. 17.3 Dosing of Levocetirizine Dihydrochloride Tablets. Do not exceed the recommended daily dose in adults and adolescents 12 years of age and older of mg once daily in the evening. In children to 11 years of age the recommended dose is 2.5 mg once daily in the evening. Advise patients to not ingest more than the recommended dose of levocetirizine dihydrochloride tablets because of the increased risk of somnolence at higher doses. Pediatric use information in pediatric patients (age months to years) is approved for UCB Inc.s levocetirizine dihydrochloride drug product labeling. However, due to UCB Inc.s marketing exclusivity rights; this drug product is not labeled for such use in those pediatric patients.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Levocetirizine, the active enantiomer of cetirizine, is an anti-histamine; its principal effects are mediated via selective inhibition of H1 receptors. The antihistaminic activity of levocetirizine has been documented in variety of animal and human models. In vitro binding studies revealed that levocetirizine has an affinity for the human H1-receptor 2-fold higher than that of cetirizine (Ki 3 nmol/L vs. nmol/L, respectively). The clinical relevance of this finding is unknown.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. No carcinogenicity studies have been performed with levocetirizine. However, evaluation of cetirizine carcinogenicity studies are relevant for determination of the carcinogenic potential of levocetirizine. In 2-year carcinogenicity study, in rats, cetirizine was not carcinogenic at dietary doses up to 20 mg/kg (approximately 15 times the maximum recommended daily oral dose in adults, approximately 10 times the maximum recommended daily oral dose in children to 11 years of age and approximately 15 times the maximum recommended daily oral dose in children months to years of age on mg/m2 basis). In 2-year carcinogenicity study in mice, cetirizine caused an increased incidence of benign hepatic tumors in males at dietary dose of 16 mg/kg (approximately times the maximum recommended daily oral dose in adults, approximately times the maximum recommended daily oral dose in children to 11 years of age, and approximately times the maximum recommended daily oral dose in children months to years of age on mg/m2 basis). No increased incidence of benign tumors was observed at dietary dose of mg/kg (approximately times the maximum recommended daily oral dose in adults, equivalent to the maximum recommended daily oral dose in children to 11 years of age and approximately times the maximum recommended daily oral dose in children months to years of age on mg/m2 basis). The clinical significance of these findings during long-term use of levocetirizine 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 mice. In fertility and general reproductive performance study in mice, cetirizine did not impair fertility at an oral dose of 64 mg/kg (approximately 25 times the recommended daily oral dose in adults on mg/m2 basis).. 13.2 Animal Toxicology. Reproductive Toxicology Studies In rats and rabbits, levocetirizine was not teratogenic at oral doses up to 200 and 120 mg/kg, respectively, (approximately 320 and 390, respectively, times the maximum recommended daily oral dose in adults on mg/m2 basis). In mice, cetirizine 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 mg/m2 basis).

NURSING MOTHERS SECTION.

8.3 Nursing Mothers. No peri- and post-natal animal studies have been conducted with levocetirizine. In mice, cetirizine caused retarded pup weight gain during lactation at an oral dose in dams that was approximately 40 times the maximum recommended daily oral dose in adults on mg/m2 basis. Studies in beagle dogs indicated that approximately 3% of the dose of cetirizine was excreted in milk. Cetirizine has been reported to be excreted in human breast milk. Because levocetirizine is also expected to be excreted in human milk, use of levocetirizine in nursing mothers is not recommended.

OVERDOSAGE SECTION.

10 OVERDOSAGE. Overdosage has been reported with levocetirizine. Symptoms of overdose may include drowsiness in adults and initially agitation and restlessness, followed by drowsiness in children. There is no known specific antidote to levocetirizine. Should overdose occur, symptomatic or supportive treatment is recommended. Levocetirizine is not effectively removed by dialysis, and dialysis will be ineffective unless dialyzable agent has been concomitantly ingested. The acute maximal non-lethal oral dose of levocetirizine was 240 mg/kg in mice (approximately 190 times the maximum recommended daily oral dose in adults, approximately 230 times the maximum recommended daily oral dose in children to 11 years of age, and approximately 180 times the maximum recommended daily oral dose in children months to years of age on mg/m2 basis). In rats the maximal non--lethal oral dose was 240 mg/kg (approximately 390 times the maximum recommended daily oral dose in adults, approximately 460 times the maximum recommended daily oral dose in children to 11 years of age, and approximately 370 times the maximum recommended daily oral dose in children months to years of age on mg/m2 basis).

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL LABEL. NDC 33261-0947-30Levocetirizine Dihydrochloride Tablets5 mgFor oral administrationRx only30 TABLETS. IMAGE LABEL.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. The recommended dose of levocetirizine for the treatment of the uncomplicated skin manifestations of chronic idiopathic urticaria in patients 12 to 17 years of age is based on extrapolation of efficacy from adults 18 years of age and older [see Clinical Studies (14)]. The recommended dose of levocetirizine in patients to 11 years of age for the treatment of the symptoms of chronic idiopathic urticaria is based on cross-study comparisons of the systemic exposure of levocetirizine in adults and pediatric patients and on the safety profile of levocetirizine in both adult and pediatric patients at doses equal to or higher than the recommended dose for patients to 11 years of age. The safety of levocetirizine mg once daily was evaluated in 243 pediatric patients to 12 years of age in two placebo-controlled clinical trials lasting and weeks [see Adverse Reactions (6.1)]. The effectiveness of levocetirizine 2.5 mg once daily (6 to 11 years of age) for the treatment of the symptoms of chronic idiopathic urticaria is supported by the extrapolation of demonstrated efficacy of levocetirizine mg once daily in patients 12 years of age and older based on the pharmacokinetic comparison between adults and children. Cross-study comparisons indicate that administration of 5 mg dose of levocetirizine to to 12 year old pediatric patients resulted in about 2-fold the systemic exposure (AUC) observed when mg of levocetirizine was administered to healthy adults. Therefore, in children to 11 years of age the recommended dose of 2.5 mg once daily should not be exceeded. [see Dosage and Administration (2.2); Clinical Studies (14); and Clinical Pharmacology (12.3)]. Pediatric use information in pediatric patients (age months to years) is approved for UCB Inc.s levocetirizine dihydrochloride drug product labeling. However, due to UCB Inc.s marketing exclusivity rights; this drug product is not labeled for such use in those pediatric patients.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. Studies in adult healthy subjects showed that levocetirizine at doses of 2.5 mg and mg inhibited the skin wheal and flare caused by the intradermal injection of histamine. In contrast, dextrocetirizine exhibited no clear change in the inhibition of the wheal and flare reaction. Levocetirizine at dose of mg inhibited the wheal and flare caused by intradermal injection of histamine in 14 pediatric subjects (aged to 11 years) and the activity persisted for at least 24 hours. The clinical relevance of histamine wheal skin testing is unknown. QT/QTc study using single dose of 30 mg of levocetirizine did not demonstrate an effect on the QTc interval. While single dose of levocetirizine had no effect, the effects of levocetirizine may not be at steady state following single dose. The effect of levocetirizine on the QTc interval following multiple dose administration is unknown. Levocetirizine is not expected to have QT/QTc effects because of the results of QTc studies with cetirizine and the long postmarketing history of cetirizine without reports of QT prolongation.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Levocetirizine exhibited linear pharmacokinetics over the therapeutic dose range in adult healthy subjects. Absorption Levocetirizine is rapidly and extensively absorbed following oral administration. In adults, peak plasma concentrations are achieved 0.9 hour after administration of the oral tablet. The accumulation ratio following daily oral administration is 1.12 with steady state achieved after days. Peak concentrations are typically 270 ng/mL and 308 ng/mL following single and repeated mg once daily dose, respectively. Food had no effect on the extent of exposure (AUC) of the levocetirizine tablet, but Tmax was delayed by about 1.25 hours and Cmax was decreased by about 36% after administration with high fat meal; therefore, levocetirizine can be administered with or without food.A dose of mg (10 mL) of levocetirizine dihydrochloride oral solution is bioequivalent to 5 mg dose of levocetirizine dihydrochloride tablets. Following oral administration of 5 mg dose of levocetirizine dihydrochloride oral solution to healthy adult subjects, the mean peak plasma concentrations were achieved approximately 0.5 hour post-dose. Distribution The mean plasma protein binding of levocetirizine in vitro ranged from 91 to 92%, independent of concentration in the range of 90 to 5000 ng/mL, which includes the therapeutic plasma levels observed. Following oral dosing, the average apparent volume of distribution is approximately 0.4 L/kg, representative of distribution in total body water. Metabolism The extent of metabolism of levocetirizine in humans is less than 14% of the dose and therefore differences resulting from genetic polymorphism or concomitant intake of hepatic drug metabolizing enzyme inhibitors are expected to be negligible. Metabolic pathways include aromatic oxidation, N- -and O-dealkylation, and taurine conjugation. Dealkylation pathways are primarily mediated by CYP 3A4 while aromatic oxidation involves multiple and/or unidentified CYP isoforms. Elimination The plasma half-life in adult healthy subjects was about to hours after administration of oral tablets and oral solution, and the mean oral total body clearance for levocetirizine was approximately 0.63 mL/kg/min. The major route of excretion of levocetirizine and its metabolites is via urine, accounting for mean of 85.4% of the dose. Excretion via feces accounts for only 12.9% of the dose. Levocetirizine is excreted both by glomerular filtration and active tubular secretion. Renal clearance of levocetirizine correlates with that of creatinine clearance. In patients with renal impairment the clearance of levocetirizine is reduced [see Dosage and Administration (2.3)]. Drug Interaction Studies In vitro data on metabolite interaction indicate that levocetirizine is unlikely to produce, or be subject to metabolic interactions. Levocetirizine at concentrations well above Cmax level achieved within the therapeutic dose ranges is not an inhibitor of CYP isoenzymes 1A2, 2C9, 2C19, 2A1, 2D6, 2E1, and 3A4, and is not an inducer of UGT1A or CYP isoenzymes 1A2, 2C9 and 3A4. No formal in vivo drug interaction studies have been performed with levocetirizine. Studies have been performed with the racemic cetirizine [see Drug Interactions (7)]. Pediatric Patients Data from pediatric pharmacokinetic study with oral administration of single dose of mg levocetirizine in 14 children age to 11 years with body weight ranging between 20 and 40 kg show that Cmax and AUC values are about 2-fold greater than that reported in healthy adult subjects in cross-study comparison. The mean Cmax was 450 ng/mL, occurring at mean time of 1.2 hours, weight-normalized, total body clearance was 30% greater, and the elimination half-life 24% shorter in this pediatric population than in adults. Dedicated pharmacokinetic studies have not been conducted in pediatric patients younger than years of age. Pharmacokinetic information in pediatric patients (age to years) is approved for UCB Inc.s levocetirizine dihydrochloride drug product labeling. However, due to UCB Inc.s marketing exclusivity rights; this drug product is not labeled for such use in those pediatric patients. Geriatric Patients Limited pharmacokinetic data are available in elderly subjects. Following once daily repeat oral administration of 30 mg levocetirizine for days in elderly subjects (65 to 74 years of age), the total body clearance was approximately 33% lower compared to that in younger adults. The disposition of racemic cetirizine has been shown to be dependent on renal function rather than on age. This finding would also be applicable for levocetirizine, as levocetirizine and cetirizine are both predominantly excreted in urine. Therefore, the levocetirizine dose should be adjusted in accordance with renal function in elderly patients [see Dosage and Administration (2)]. Gender Pharmacokinetic results for 77 patients (40 men, 37 women) were evaluated for potential effect of gender. The half-life was slightly shorter in women (7.08 +- 1.72 hr) than in men (8.62 +- 1.84 hr); however, the body weight-adjusted oral clearance in women (0.67 +- 0.16 mL/min/kg) appears to be comparable to that in men (0.59 +- 0.12 mL/min/kg). The same daily doses and dosing intervals are applicable for men and women with normal renal function. Race The effect of race on levocetirizine has not been studied. As levocetirizine is primarily renally excreted, and there are no important racial differences in creatinine clearance, pharmacokinetic characteristics of levocetirizine are not expected to be different across races. No race-related differences in the kinetics of racemic cetirizine have been observed. Renal Impairment Levocetirizine exposure (AUC) exhibited 1.8-, 3.2-, 4.3-, and 5.7-fold increase in mild, moderate, severe, renal impaired, and end-stage renal disease patients, respectively, compared to healthy subjects. The corresponding increases of half-life estimates were 1.4-, 2-, 2.9-, and 4-fold, respectively. The total body clearance of levocetirizine after oral dosing was correlated to the creatinine clearance and was progressively reduced based on severity of renal impairment. Therefore, it is recommended to adjust the dose and dosing intervals of levocetirizine based on creatinine clearance in patients with mild, moderate, or severe renal impairment. In end-stage renal disease patients (CLCR 10 mL/min) levocetirizine is contraindicated. The amount of levocetirizine removed during standard 4-hour hemodialysis procedure was <10%. The dosage of levocetirizine should be reduced in patients with mild renal impairment. Both the dosage and frequency of administration should be reduced in patients with moderate or severe renal impairment [see Dosage and Administration (2.4)]. Hepatic Impairment Levocetirizine has not been studied in patients with hepatic impairment. The non-renal clearance (indicative of hepatic contribution) was found to constitute about 28% of the total body clearance in healthy adult subjects after oral administration. As levocetirizine is mainly excreted unchanged by the kidney, it is unlikely that the clearance of levocetirizine is significantly decreased in patients with solely hepatic impairment [see Dosage and Administration (2)].

PREGNANCY SECTION.

8.1 Pregnancy. Pregnancy Category There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, levocetirizine should be used during pregnancy only if clearly needed. Teratogenic Effects: In rats and rabbits, levocetirizine was not teratogenic at oral doses approximately 320 and 390, respectively, times the maximum recommended daily oral dose in adults on mg/m2 basis.

RECENT MAJOR CHANGES SECTION.

RECENT MAJOR CHANGES. Warnings and Precautions, Urinary Retention (5.2) [09/2012].

SPL UNCLASSIFIED SECTION.

1.3 Chronic Idiopathic Urticaria. Levocetirizine dihydrochloride tablets are indicated for the treatment of the uncomplicated skin manifestations of chronic idiopathic urticaria in adults and children years of age and older. Pediatric use information in pediatric patients (age months to years) is approved for UCB Inc.s levocetirizine dihydrochloride drug product labeling. However, due to UCB Inc.s marketing exclusivity rights; this drug product is not labeled for such use in those pediatric patients.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Renal Impairment Because levocetirizine is substantially excreted by the kidneys, the risk of adverse reactions to this drug may be greater in patients with impaired renal function (8.6 and 12.3). Pediatric Use Do not exceed the recommended doses of 2.5 mg once daily in children to 11 years. Systemic exposure with this dose in pediatric age groups is comparable to that from 5 mg once daily dose in adults. (12.3). Pediatric use information in pediatric patients (age months to years) is approved for UCB Inc.s levocetirizine dihydrochloride drug product labeling. However, due to UCB Inc.s marketing exclusivity rights; this drug product is not labeled for such use in those pediatric patients 8.1 Pregnancy. Pregnancy Category There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, levocetirizine should be used during pregnancy only if clearly needed. Teratogenic Effects: In rats and rabbits, levocetirizine was not teratogenic at oral doses approximately 320 and 390, respectively, times the maximum recommended daily oral dose in adults on mg/m2 basis.. 8.3 Nursing Mothers. No peri- and post-natal animal studies have been conducted with levocetirizine. In mice, cetirizine caused retarded pup weight gain during lactation at an oral dose in dams that was approximately 40 times the maximum recommended daily oral dose in adults on mg/m2 basis. Studies in beagle dogs indicated that approximately 3% of the dose of cetirizine was excreted in milk. Cetirizine has been reported to be excreted in human breast milk. Because levocetirizine is also expected to be excreted in human milk, use of levocetirizine in nursing mothers is not recommended.. 8.4 Pediatric Use. The recommended dose of levocetirizine for the treatment of the uncomplicated skin manifestations of chronic idiopathic urticaria in patients 12 to 17 years of age is based on extrapolation of efficacy from adults 18 years of age and older [see Clinical Studies (14)]. The recommended dose of levocetirizine in patients to 11 years of age for the treatment of the symptoms of chronic idiopathic urticaria is based on cross-study comparisons of the systemic exposure of levocetirizine in adults and pediatric patients and on the safety profile of levocetirizine in both adult and pediatric patients at doses equal to or higher than the recommended dose for patients to 11 years of age. The safety of levocetirizine mg once daily was evaluated in 243 pediatric patients to 12 years of age in two placebo-controlled clinical trials lasting and weeks [see Adverse Reactions (6.1)]. The effectiveness of levocetirizine 2.5 mg once daily (6 to 11 years of age) for the treatment of the symptoms of chronic idiopathic urticaria is supported by the extrapolation of demonstrated efficacy of levocetirizine mg once daily in patients 12 years of age and older based on the pharmacokinetic comparison between adults and children. Cross-study comparisons indicate that administration of 5 mg dose of levocetirizine to to 12 year old pediatric patients resulted in about 2-fold the systemic exposure (AUC) observed when mg of levocetirizine was administered to healthy adults. Therefore, in children to 11 years of age the recommended dose of 2.5 mg once daily should not be exceeded. [see Dosage and Administration (2.2); Clinical Studies (14); and Clinical Pharmacology (12.3)]. Pediatric use information in pediatric patients (age months to years) is approved for UCB Inc.s levocetirizine dihydrochloride drug product labeling. However, due to UCB Inc.s marketing exclusivity rights; this drug product is not labeled for such use in those pediatric patients. 8.5 Geriatric Use. Clinical studies of levocetirizine for each approved indication did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently than younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy.. 8.6 Renal Impairment. Levocetirizine is known to be substantially excreted by the kidneys and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection and it may be useful to monitor renal function [see Dosage and Administration (2) and Clinical Pharmacology (12.3)].. 8.7 Hepatic Impairment. As levocetirizine is mainly excreted unchanged by the kidneys, it is unlikely that the clearance of levocetirizine is significantly decreased in patients with solely hepatic impairment [see Clinical Pharmacology (12.3)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Avoid engaging in hazardous occupations requiring complete mental alertness such as driving or operating machinery when taking levocetirizine dihydrochloride tablets (5.1). Avoid concurrent use of alcohol or other central nervous system depressants with levocetirizine dihydrochloride tablets (5.1). Use with caution in patients with predisposing factors of urinary retention (e.g. spinal cord lesion, prostatic hyperplasia). Discontinue levocetirizine dihydrochloride tablets if urinary retention occurs (5.2).. Avoid engaging in hazardous occupations requiring complete mental alertness such as driving or operating machinery when taking levocetirizine dihydrochloride tablets (5.1). Avoid concurrent use of alcohol or other central nervous system depressants with levocetirizine dihydrochloride tablets (5.1). Use with caution in patients with predisposing factors of urinary retention (e.g. spinal cord lesion, prostatic hyperplasia). Discontinue levocetirizine dihydrochloride tablets if urinary retention occurs (5.2).. 5.1 Somnolence. In clinical trials the occurrence of somnolence, fatigue, and asthenia has been reported in some patients under therapy with levocetirizine dihydrochloride tablets. Patients should be cautioned against engaging in hazardous occupations requiring complete mental alertness, and motor coordination such as operating machinery or driving motor vehicle after ingestion of levocetirizine dihydrochloride tablet. Concurrent use of levocetirizine dihydrochloride tablets with alcohol or other central nervous system depressants should be avoided because additional reductions in alertness and additional impairment of central nervous system performance may occur.. 5.2 Urinary Retention. Urinary retention has been reported postmarketing with levocetirizine dihydrochloride tablets. Levocetirizine dihydrochloride tablets should be used with caution in patients with predisposing factors of urinary retention (e.g. spinal cord lesion, prostatic hyperplasia) as levocetirizine dihydrochloride tablets may increase the risk of urinary retention. Discontinue levocetirizine dihydrochloride tablets if urinary retention occurs.