ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. Use of levocetirizine dihydrochloride oral solution 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. In subjects to years of age, the most common adverse reactions (rate >=2% and placebo) were pyrexia, diarrhea, vomiting, and otitis media. In subjects to 11 months of age, the most common adverse reactions (rate >=3% and placebo) were diarrhea and constipation. (6.1). To report SUSPECTED ADVERSE REACTIONS, contact Hetero Labs Limited at 1-866-495-1995 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 dihydrochloride in 2,708 patients with allergic rhinitis or chronic idiopathic urticaria in 14 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 1,896 patients (825 males and 1,071 females aged 12 years and older) were treated with levocetirizine dihydrochloride 2.5, 5, 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 with allergic rhinitis (162 males and 81 females to 12 years of age) were treated with levocetirizine dihydrochloride mg once daily for to weeks, one clinical trial in which 114 children (65 males and 49 females to years of age) with allergic rhinitis or chronic idiopathic urticaria were treated with levocetirizine dihydrochloride 1.25 mg twice daily for weeks, and one clinical trial in which 45 children (28 males and 17 females to 11 months of age) with symptoms of allergic rhinitis or chronic urticaria were treated with levocetirizine dihydrochloride 1.25 mg once daily for 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) with allergic rhinitis were exposed to treatment with levocetirizine dihydrochloride mg once daily. Long term safety data are also available from an 18-month trial in 255 levocetirizine dihydrochloride-treated subjects 12 to 24 months of age. 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 dihydrochloride 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 dihydrochloride showed dose ordering between tested doses of 2.5, 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 dihydrochloride 2.5 mg or mg in eight placebo-controlled clinical trials and that were more common with levocetirizine dihydrochloride than placebo. Table 1: Adverse Reactions Reported in >=2% of Subjects Aged 12 Years and Older Exposed to Levocetirizine Dihydrochloride 2.5 mg or mg Once Daily in Placebo-Controlled Clinical Trials to Weeks in Duration Adverse Reactions Levocetirizine Dihydrochloride 2.5 mg(n 421) Levocetirizine Dihydrochloride mg(n 1,070) 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%) Rounded to the closest unit percentage 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 dihydrochloride 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 dihydrochloride 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 dihydrochloride mg in placebo-controlled clinical trials and that were more common with levocetirizine dihydrochloride than placebo. Table 2: Adverse Reactions Reported in >=2% of Subjects Aged to 12 Years Exposed to Levocetirizine Dihydrochloride mg Once Daily in Placebo-Controlled Clinical Trials and Weeks in Duration Adverse Reactions Levocetirizine Dihydrochloride mg(n 243) Placebo(n 240) Pyrexia 10 (4%) (2%) Cough (3%) (<1%) Somnolence (3%) (<1%) Epistaxis (2%) (<1%) Rounded to the closest unit percentage Pediatric Patients to Years of Age total of 114 pediatric patients to years of age received levocetirizine dihydrochloride 1.25 mg twice daily in two week placebo-controlled double-blind safety trial. The mean age of the patients was 3.8 years, 32% were to years of age, 71% were Caucasian and 18% were Black. Table lists adverse reactions that were reported in greater than or equal to 2% of subjects aged to years exposed to levocetirizine dihydrochloride 1.25 mg twice daily in the placebo-controlled safety trial and that were more common with levocetirizine dihydrochloride than placebo. Table 3: Adverse Reactions Reported in >=2% of Subjects Aged to Years Exposed to Levocetirizine Dihydrochloride 1.25 mg Twice Daily in 2-Week Placebo-Controlled Clinical Trial Adverse Reactions Levocetirizine Dihydrochloride 1.25 mg Twice Daily(n 114) Placebo(n 59) Pyrexia (4%) (2%) Diarrhea (4%) (3%) Vomiting (4%) (3%) Otitis Media (3%) (0%) Rounded to the closest unit percentage Pediatric Patients to 11 Months of Age total of 45 pediatric patients to 11 months of age received levocetirizine dihydrochloride 1.25 mg once daily in two week placebo-controlled double-blind safety trial. The mean age of the patients was months, 51% were Caucasian and 31% were Black. Adverse reactions that were reported in more than subject (i.e. greater than or equal to 3% of subjects) aged to 11 months exposed to levocetirizine dihydrochloride 1.25 mg once daily in the placebo-controlled safety trial and that were more common with levocetirizine dihydrochloride than placebo included diarrhea and constipation which were reported in (13%) and (4%) and (7%) and (4%) children in the levocetirizine dihydrochloride and placebo-treated groups, respectively. Long-Term Clinical Trials Experience In two controlled clinical trials, 428 patients (190 males and 238 females) aged 12 years and older were treated with levocetirizine dihydrochloride 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 dihydrochloride 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 allergic rhinitis or chronic idiopathic urticaria. Laboratory Test Abnormalities Elevations 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, the following adverse reactions have also been identified during postapproval use of levocetirizine dihydrochloride. Because these reactions 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. Cardiac disorders: palpitations, tachycardia Ear and labyrinth disorders: vertigo Eye disorders: blurred vision, visual disturbances Gastrointestinal disorders: nausea, vomiting General disorders and administration site conditions: edema Hepatobiliary disorders: hepatitis Immune system disorders: anaphylaxis and hypersensitivity Metabolism and nutrition disorders: increased appetite Musculoskeletal, connective tissues, and bone disorders: arthralgia, myalgia Nervous system disorders: dizziness, dysgeusia, febrile seizure, movement disorders (including dystonia and oculogyric crisis), paresthesia, seizure (reported in subjects with and without known seizure disorder), tremor Psychiatric disorders: aggression and agitation, depression, hallucinations, insomnia, nightmare, suicidal ideation Renal and urinary disorders: dysuria, urinary retention Respiratory, thoracic, and mediastinal disorders: dyspnea Skin and subcutaneous tissue disorders: angioedema, fixed drug eruption, pruritus, rash and urticaria Besides these reactions reported under treatment with levocetirizine dihydrochloride 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 dihydrochloride. Cardiac disorders: severe hypotension Gastrointestinal disorders: cholestasis Nervous system disorders: extrapyramidal symptoms, myoclonus, orofacial dyskinesia, tic Pregnancy, puerperium and perinatal conditions: stillbirth Renal and urinary disorders: glomerulonephritis Skin and subcutaneous tissue disorders: acute generalized exanthematous pustulosis (AGEP); rebound pruritus pruritus within few days after discontinuation of cetirizine, usually after long-term use (e.g. months to years) of cetirizine.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. Levocetirizine dihydrochloride oral solution is clear, colorless liquid containing 0.5 mg of levocetirizine dihydrochloride per mL. Oral Solution available in oz (148 mL) polypropylene container (with FSE wad) NDC 31722-659-31 Storage: Store at 20 to 25C (68 to 77F); excursions permitted to 15 to 30C (59 to 86F) [see USP Controlled Room Temperature].

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 is 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 40, 40, 25, and 10 times the MRHDs in adults, children to 11 years of age, children to years, and children months to years of age, respectively, 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 15, 15, 9, and times the MRHDs in adults, children to 11 years of age, children to years, and children months to years of age, respectively, on mg/m2 basis). No increased incidence of benign tumors was observed at dietary dose of mg/kg (approximately 4, 4, 2, and times the MRHDs in adults, children to 11 years of age, children to years, and children months to years of age, respectively 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. Fertility and reproductive performance were unaffected in male and female mice and rats that received cetirizine at oral doses up to 64 and 200 mg/kg/day, respectively (approximately 60 and 390 times the MRHD 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 antihistamine; 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. 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 5,000 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 CYP3A4 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 (2.2)]. 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. retrospective population pharmacokinetic analysis was conducted in 323 subjects (181 children to years of age, 18 children to 11 years of age, and 124 adults 18 to 55 years of age) who received single or multiple doses of levocetirizine ranging from 1.25 mg to 30 mg. Data generated from this analysis indicated that dministration of 1.25 mg once daily to children months to years of age results in plasma concentrations similar to those of adults receiving mg once daily. 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 dihydrochloride oral solution 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-, 2.0-, 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 dihydrochloride 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 (2.2)]. Hepatic impairment Levocetirizine dihydrochloride 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. 14.1 Perennial Allergic Rhinitis. Adults and Adolescents 12 Years of Age and Older The efficacy of levocetirizine dihydrochloride was evaluated in four randomized, placebo-controlled, double-blind clinical trials in adult and adolescent patients 12 years and older with symptoms of perennial allergic rhinitis. The four clinical trials include two dose-ranging trials of weeks duration and two efficacy trials (one 6-week and one 6-month) in patients with perennial allergic rhinitis. These trials included total of 1,729 patients (752 males and 977 females) of whom 227 were adolescents 12 to 17 years of age. Efficacy was assessed using total symptom score from patient recording of symptoms (sneezing, rhinorrhea, nasal pruritus, and ocular pruritus) in three studies and symptoms (sneezing, rhinorrhea, nasal pruritus, ocular pruritus, and nasal congestion) in one study. Patients recorded symptoms using 0 to categorical severity scale (0 absent, = mild, = moderate, = severe) once daily in the evening reflective of the 24 hour treatment period. The primary endpoint was the mean total symptom score averaged over the first week and over weeks for perennial allergic rhinitis trials. The two dose-ranging trials were conducted to evaluate the efficacy of levocetirizine dihydrochloride 2.5, 5, and 10 mg once daily in the evening. These trials were weeks in duration and included patients with perennial allergic rhinitis. In these trials, each of the three doses of levocetirizine dihydrochloride demonstrated greater decrease in the reflective total symptom score than placebo and the difference was statistically significant for all three doses in the two studies. Results for one of these trials are shown in Table 4. Table 4: Mean Reflective Total Symptom Score in Allergic Rhinitis Dose-Ranging Trials Treatment Baseline On Treatment Adjusted Mean Difference from PlaceboEstimate 95% CI p-value Perennial Allergic Rhinitis Trial Reflective total symptom score Levocetirizine dihydrochloride 2.5 mg 133 7.14 4.12 1.17 (0.71, 1.63) <0.001 Levocetirizine dihydrochloride mg 127 7.18 4.07 1.22 (0.76, 1.69) <0.001 Levocetirizine dihydrochloride 10 mg 129 7.58 4.19 1.10 (0.64, 1.57) <0.001 Placebo 128 7.22 5.29 Total symptom score is the sum of individual symptoms of sneezing, rhinorrhea, nasal pruritus, and ocular pruritus as assessed by patients on 0 to categorical severity scale. One clinical trial evaluated the efficacy of levocetirizine dihydrochloride mg once daily in the evening compared to placebo in patients with perennial allergic rhinitis over 6-week treatment period. Another trial conducted over 6-month treatment period assessed efficacy at weeks. Levocetirizine dihydrochloride mg demonstrated greater decrease from baseline in the reflective total symptom score than placebo and the difference from placebo was statistically significant. Results of the former are shown in Table 5. Table 5: Mean Reflective Total Symptom Score in Allergic Rhinitis Trials Treatment Baseline On Treatment Adjusted MeanDifference from PlaceboEstimate 95% CI p-value Perennial Allergic Rhinitis Trial Reflective total symptom scoreLevocetirizine dihydrochloride mg 150 7.69 3.93 1.17 (0.70, 1.64) <0.001 Placebo 142 7.44 5.10 Total symptom score is the sum of individual symptoms of sneezing, rhinorrhea, nasal pruritus, and ocular pruritus as assessed by patients on 0 to categorical severity scale. Onset of action was evaluated in two environmental exposure unit studies in allergic rhinitis patients with single dose of levocetirizine dihydrochloride 2.5 or mg. Levocetirizine dihydrochloride mg was found to have an onset of action hour after oral intake. Onset of action was also assessed from the daily recording of symptoms in the evening before dosing in the allergic rhinitis trials. In these trials, onset of effect was seen after day of dosing. Pediatric Patients Less than 12 Years of Age There are no clinical efficacy trials with levocetirizine dihydrochloride 2.5 mg once daily in pediatric patients under 12 years of age, and no clinical efficacy trials with levocetirizine dihydrochloride 1.25 mg once daily in pediatric patients months to years of age. The clinical efficacy of levocetirizine dihydrochloride in pediatric patients under 12 years of age has been extrapolated from adult clinical efficacy trials based on pharmacokinetic comparisons [see Use in Specific Populations 8.4)]. 14.2 Chronic Idiopathic Urticaria. Adult Patients 18 Years of Age and Older The efficacy of levocetirizine dihydrochloride 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 dihydrochloride 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 dihydrochloride 2.5, 5, and 10 mg once daily in the evening. In this trial, each of the three doses of levocetirizine dihydrochloride demonstrated greater decrease in the reflective pruritus severity score than placebo and the difference was statistically significant for all three doses (see Table 6). The single dose level trial evaluated the efficacy of levocetirizine dihydrochloride mg once daily in the evening compared to placebo in patients with chronic idiopathic urticaria over 4-week treatment period. Levocetirizine dihydrochloride 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 6). Table 6: Mean Reflective Pruritus Severity Score in Chronic Idiopathic Urticaria Trials Treatment Baseline On Treatment Adjusted MeanDifference from PlaceboEstimate95% CIp-valueDose-Ranging Trial Reflective pruritus severity scoreLevocetirizine dihydrochloride2.5 mg 69 2.08 1.02 0.82 (0.58, 1.06) <0.001 Levocetirizine dihydrochloride5 mg 62 2.07 0.92 0.91 (0.66, 1.16) <0.001 Levocetirizine dihydrochloride 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 scoreLevocetirizine dihydrochloride mg 80 2.07 0.94 0.62 (0.38, 0.86) <0.001 Placebo 82 2.06 1.56 Pediatric Patients There 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 oral solution is contraindicated in:. Patients with known hypersensitivity to levocetirizine or any of the ingredients of levocetirizine dihydrochloride oral solution or to cetirizine (4.1) Patients with end-stage renal disease at less than 10 mL/min creatinine clearance or patients undergoing hemodialysis (4.2) Children months to 11 years of age with renal impairment (4.3) 4.1 Patients with Known Hypersensitivity. Patients with known hypersensitivity to levocetirizine or any of the ingredients of levocetirizine dihydrochloride oral solution, 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 oral solution is an orally active H1-receptor antagonist. The chemical name is 2-[2-[4[(R)-(4-chlorophenyl) -phenyl-methyl] piperazine-1-yl]ethoxy] acetic acid. Dihydrochloride. Levocetirizine dihydrochloride is the enantiomer of cetirizine hydrochloride, racemic compound with antihistaminic properties. The empirical formula of levocetirizine dihydrochloride is C21H27Cl3N2O3. The molecular weight is 461.8 and the chemical structure is shown below:Levocetirizine dihydrochloride USP is white to almost white powder and is freely soluble in water and in methanolLevocetirizine dihydrochloride 0.5 mg/mL oral solution is formulated as an immediate release, clear, colorless liquid. Inactive ingredients are: artificial grape flavor, glacial acetic acid, glycerin, maltitol solution, methyl paraben, propyl paraben, purified water, saccharin sodium and sodium acetate trihydrate.. levostructure.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE ADMINISTRATION. Levocetirizine dihydrochloride is available as 2.5 mg/5 mL (0.5 mg/mL) oral solution. Levocetirizine dihydrochloride oral solution can be taken without regard to food consumption.. Perennial Allergic Rhinitis(2.1) Children months to years of age: 1.25 mg (1/2 teaspoon oral solution) (2.5 mL) once daily in the evening Chronic Idiopathic Urticaria (2.2) Adults and children 12 years of age and older: mg once daily in the evening Children to 11 years of age: 2.5 mg once daily in the evening Children months to years of age: 1.25 mg (1/2 teaspoon oral solution) (2.5 mL) once daily in the evening Renal Impairment Adjust the dose in patients 12 years of age and older with decreased renal function (12.3) 2.1 Perennial Allergic Rhinitis. Children months to Years of Age The recommended initial dose of levocetirizine dihydrochloride is 1.25 mg (1/2 teaspoon oral solution) (2.5 mL) once daily in the evening. The 1.25 mg once daily dose should not be exceeded based on comparable exposure to adults receiving mg [see Clinical Pharmacology 12.3)]. 2.2 Chronic Idiopathic Urticaria. Adults and Children 12 Years of Age and Older The recommended dose of levocetirizine dihydrochloride is mg (2 teaspoons [10 mL] oral solution) once daily in the evening. Some patients may be adequately controlled by 2.5 mg (1 teaspoon [5 mL] oral solution) once daily in the evening. Children to 11 Years of Age The recommended dose of levocetirizine dihydrochloride is 2.5 mg (1 teaspoon [5 mL] oral solution) 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)]. Children months to Years of Age The recommended initial dose of levocetirizine dihydrochloride is 1.25 mg (1/2 teaspoon oral solution) (2.5 mL) once daily in the evening. The 1.25 mg once daily dose should not be exceeded based on comparable exposure to adults receiving mg [see Clinical Pharmacology (12.3)]. 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 oral solution. 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.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS STRENGTHS. Levocetirizine dihydrochloride oral solution is clear, colorless liquid containing 0.5 mg of levocetirizine dihydrochloride per mL.. Immediate release oral solution, 2.5 mg per mL (0.5 mg per mL) (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 dihydrochloride 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.

INDICATIONS & USAGE SECTION.

1 INDICATIONS USAGE. Levocetirizine dihydrochloride oral solution is histamine H1-receptor antagonist indicated for: The relief of symptoms associated with perennial allergic rhinitis(1.1) The treatment of the uncomplicated skin manifestations of chronic idiopathic urticaria (1.2) 1.1 Perennial Allergic Rhinitis. Levocetirizine dihydrochloride oral solution is indicated for the relief of symptoms associated with perennial allergic rhinitis in children months to years of age.. 1.2 Chronic Idiopathic Urticaria. Levocetirizine dihydrochloride oral solution is indicated for the treatment of the uncomplicated skin manifestations of chronic idiopathic urticaria in adults and children months of age and older.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. 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 oral solution. Concomitant Use of Alcohol and other Central Nervous System Depressants Instruct patients to avoid concurrent use of levocetirizine dihydrochloride oral solution with alcohol or other central nervous system depressants because additional reduction in mental alertness may occur. Dosing of Levocetirizine Dihydrochloride Oral Solution 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. In children months to years of age, the recommended dose is 1.25 mg once daily in the evening. Advise patients to not ingest more than the recommended dose of levocetirizine dihydrochloride oral solution because of the increased risk of somnolence at higher doses. Manufactured for: Camber Pharmaceuticals, Inc. Piscataway, NJ 08854 By: HETEROTM Hetero Labs Limited Jeedimetla, Hyderabad 500 055, India. Revised: 04/2019 camberlogo.

LACTATION SECTION.

8.2 Lactation. Risk Summary There are no data on the presence of levocetirizine in human milk, the effects on the breastfed infant, or the effects on milk production. However, cetirizine has been reported to be present in human breast milk. In mice and beagle dogs, studies indicated that cetirizine was excreted in milk [see Data] When drug is present in animal milk, it is likely the drug will be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for levocetirizine and any potential adverse effects on the breastfed child from levocetirizine or from the underlying maternal condition. Data Animal Data Cetirizine was detected in the milk of mice. No adverse developmental effects on pups were seen when cetirizine was administered orally to dams during lactation at dose that was approximately 25 times the MRHD in adults [see Use in Specific Populations (8.1)]. Studies in beagle dogs indicated that approximately 3% of the dose of cetirizine was excreted in milk. The concentration of drug in animal milk does not necessarily predict the concentration of drug in human milk.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Levocetirizine, the active enantiomer of cetirizine, is an antihistamine; 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 is 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 40, 40, 25, and 10 times the MRHDs in adults, children to 11 years of age, children to years, and children months to years of age, respectively, 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 15, 15, 9, and times the MRHDs in adults, children to 11 years of age, children to years, and children months to years of age, respectively, on mg/m2 basis). No increased incidence of benign tumors was observed at dietary dose of mg/kg (approximately 4, 4, 2, and times the MRHDs in adults, children to 11 years of age, children to years, and children months to years of age, respectively 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. Fertility and reproductive performance were unaffected in male and female mice and rats that received cetirizine at oral doses up to 64 and 200 mg/kg/day, respectively (approximately 60 and 390 times the MRHD in adults on mg/m2 basis).

OVERDOSAGE SECTION.

10 OVERDOSAGE. Overdosage has been reported with levocetirizine dihydrochloride. Symptoms of overdose may include drowsiness in adults. In children agitation and restlessness may initially occur, followed by drowsiness. There is no known specific antidote to levocetirizine dihydrochloride. Should overdose occur, symptomatic or supportive treatment is recommended. Levocetirizine dihydrochloride 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. Levocetirizine Dihydrochloride Oral Solution 2.5 mg/ mL (0.5 mg/mL) container label Levocetirizine Dihydrochloride Oral Solution 2.5 mg/ mL (0.5 mg/mL) carton label. levocontlabel. levocartonlabel.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. The recommended dose of levocetirizine dihydrochloride for the treatment of the uncomplicated skin manifestations of chronic idiopathic urticaria in patients months 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 dihydrochloride in patients months to years of age for the treatment of the symptoms of perennial allergic rhinitis and months to 11 years of age with chronic idiopathic urticaria is based on cross-study comparisons of the systemic exposure of levocetirizine dihydrochloride in adults and pediatric patients and on the safety profile of levocetirizine dihydrochloride in both adult and pediatric patients at doses equal to or higher than the recommended dose for patients months to 11 years of age. The safety of levocetirizine dihydrochloride mg once daily was evaluated in 243 pediatric patients to 12 years of age in two placebo-controlled clinical trials lasting and weeks. The safety of levocetirizine dihydrochloride 1.25 mg twice daily was evaluated in one 2-week clinical trial in 114 pediatric patients to years of age and the safety of levocetirizine dihydrochloride 1.25 mg once daily was evaluated in one 2-week clinical trial in 45 pediatric patients to 11 months of age [see Adverse Reactions (6.1)]. The effectiveness of levocetirizine dihydrochloride 1.25 mg once daily (6 months to years of age) and 2.5 mg once daily (6 to 11 years of age) for the treatment of the symptoms of perennial allergic rhinitis and chronic idiopathic urticaria is supported by the extrapolation of demonstrated efficacy of levocetirizine dihydrochloride 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 dihydrochloride to to 12 year old pediatric patients resulted in about 2-fold the systemic exposure (AUC) observed when mg of levocetirizine dihydrochloride 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. In population pharmacokinetics study the administration of 1.25 mg once daily in children months to years of age resulted in systemic exposure comparable to mg once daily in adults [see Dosage and Administration (2.2), Clinical Studies (14), and Clinical Pharmacology (12.3)].

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. 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 5,000 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 CYP3A4 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 (2.2)]. 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. retrospective population pharmacokinetic analysis was conducted in 323 subjects (181 children to years of age, 18 children to 11 years of age, and 124 adults 18 to 55 years of age) who received single or multiple doses of levocetirizine ranging from 1.25 mg to 30 mg. Data generated from this analysis indicated that dministration of 1.25 mg once daily to children months to years of age results in plasma concentrations similar to those of adults receiving mg once daily. 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 dihydrochloride oral solution 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-, 2.0-, 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 dihydrochloride 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 (2.2)]. Hepatic impairment Levocetirizine dihydrochloride 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. Risk Summary Available data from published literature and postmarketing experience with levocetirizine use in pregnant women are insufficient to identify any drug-associated risks of miscarriage, birth defects, or adverse maternal or fetal outcomes. In animal reproduction studies, there was no evidence of fetal harm with administration of levocetirizine by the oral route to pregnant rats and rabbits, during the period of organogenesis, at doses up to 390 times and 470 times, respectively, the maximum recommended human dose (MRHD) in adults. In rats treated during late gestation and the lactation period, cetirizine had no effects on pup development at oral doses up to approximately 60 times the MRHD in adults. In mice treated during late gestation and the lactation period, cetirizine administered by the oral route to the dams had no effects on pup development at dose that was approximately 25 times the MRHD in adults; however, lower pup weight gain during lactation was observed at dose that was 95 times the MRHD in adults [see Data]. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data In embryo-fetal development studies, pregnant rats received daily doses of levocetirizine up to 200 mg/kg/day from gestation days to 15 and pregnant rabbits received daily doses of levocetirizine up to 120 mg/kg/day from gestation days to 18. Levocetirizine produced no evidence of fetal harm in rats and rabbits at doses up to 390 and 470 times the MRHD, respectively (on mg/m2 basis with maternal oral doses of 200 and 120 mg/kg/day in rats and rabbits, respectively). No prenatal and postnatal development (PPND) studies in animals have been conducted with levocetirizine. In PPND study conducted in mice, cetirizine was administered at oral doses up to 96 mg/kg/day from gestation day 15 through lactation day 21. Cetirizine lowered pup body weight gain during lactation at an oral dose in dams that was approximately 95 times the MRHD (on mg/m2 basis with maternal oral dose of 96 mg/kg/day); however, there were no effects on pup weight gain at an oral dose in dams that was approximately 25 times the MRHD (on mg/m2 basis with maternal oral dose of 24 mg/kg/day). In PPND study conducted in rats, cetirizine was administered at oral doses up to 180 mg/kg/day from gestation day 17 to lactation day 22. Cetirizine did not have any adverse effects on rat dams or offspring development at doses up to approximately 60 times the MRHD (on mg/m2 basis with maternal oral dose of 30 mg/kg/day). Cetirizine caused excessive maternal toxicity at an oral dose in dams that was approximately 350 times the MRHD (on mg/m2 basis with maternal oral dose of 180 mg/kg/day).

SPL UNCLASSIFIED SECTION.

1.1 Perennial Allergic Rhinitis. Levocetirizine dihydrochloride oral solution is indicated for the relief of symptoms associated with perennial allergic rhinitis in children months to years of age.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Renal Impairment Because levocetirizine dihydrochloride is substantially excreted by the kidneys, the risk of adverse reactions to this drug may be greater in patients with impaired renal function. (8.6,12.3) Pediatric Use Do not exceed the recommended doses of 2.5 mg and 1.25 mg once daily in children to 11 years and months to years of age, respectively. Systemic exposure with these doses in respective pediatric age groups is comparable to that from 5 mg once daily dose in adults. (12.3) 8.1 Pregnancy. Risk Summary Available data from published literature and postmarketing experience with levocetirizine use in pregnant women are insufficient to identify any drug-associated risks of miscarriage, birth defects, or adverse maternal or fetal outcomes. In animal reproduction studies, there was no evidence of fetal harm with administration of levocetirizine by the oral route to pregnant rats and rabbits, during the period of organogenesis, at doses up to 390 times and 470 times, respectively, the maximum recommended human dose (MRHD) in adults. In rats treated during late gestation and the lactation period, cetirizine had no effects on pup development at oral doses up to approximately 60 times the MRHD in adults. In mice treated during late gestation and the lactation period, cetirizine administered by the oral route to the dams had no effects on pup development at dose that was approximately 25 times the MRHD in adults; however, lower pup weight gain during lactation was observed at dose that was 95 times the MRHD in adults [see Data]. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data In embryo-fetal development studies, pregnant rats received daily doses of levocetirizine up to 200 mg/kg/day from gestation days to 15 and pregnant rabbits received daily doses of levocetirizine up to 120 mg/kg/day from gestation days to 18. Levocetirizine produced no evidence of fetal harm in rats and rabbits at doses up to 390 and 470 times the MRHD, respectively (on mg/m2 basis with maternal oral doses of 200 and 120 mg/kg/day in rats and rabbits, respectively). No prenatal and postnatal development (PPND) studies in animals have been conducted with levocetirizine. In PPND study conducted in mice, cetirizine was administered at oral doses up to 96 mg/kg/day from gestation day 15 through lactation day 21. Cetirizine lowered pup body weight gain during lactation at an oral dose in dams that was approximately 95 times the MRHD (on mg/m2 basis with maternal oral dose of 96 mg/kg/day); however, there were no effects on pup weight gain at an oral dose in dams that was approximately 25 times the MRHD (on mg/m2 basis with maternal oral dose of 24 mg/kg/day). In PPND study conducted in rats, cetirizine was administered at oral doses up to 180 mg/kg/day from gestation day 17 to lactation day 22. Cetirizine did not have any adverse effects on rat dams or offspring development at doses up to approximately 60 times the MRHD (on mg/m2 basis with maternal oral dose of 30 mg/kg/day). Cetirizine caused excessive maternal toxicity at an oral dose in dams that was approximately 350 times the MRHD (on mg/m2 basis with maternal oral dose of 180 mg/kg/day). 8.2 Lactation. Risk Summary There are no data on the presence of levocetirizine in human milk, the effects on the breastfed infant, or the effects on milk production. However, cetirizine has been reported to be present in human breast milk. In mice and beagle dogs, studies indicated that cetirizine was excreted in milk [see Data] When drug is present in animal milk, it is likely the drug will be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for levocetirizine and any potential adverse effects on the breastfed child from levocetirizine or from the underlying maternal condition. Data Animal Data Cetirizine was detected in the milk of mice. No adverse developmental effects on pups were seen when cetirizine was administered orally to dams during lactation at dose that was approximately 25 times the MRHD in adults [see Use in Specific Populations (8.1)]. Studies in beagle dogs indicated that approximately 3% of the dose of cetirizine was excreted in milk. The concentration of drug in animal milk does not necessarily predict the concentration of drug in human milk. 8.4 Pediatric Use. The recommended dose of levocetirizine dihydrochloride for the treatment of the uncomplicated skin manifestations of chronic idiopathic urticaria in patients months 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 dihydrochloride in patients months to years of age for the treatment of the symptoms of perennial allergic rhinitis and months to 11 years of age with chronic idiopathic urticaria is based on cross-study comparisons of the systemic exposure of levocetirizine dihydrochloride in adults and pediatric patients and on the safety profile of levocetirizine dihydrochloride in both adult and pediatric patients at doses equal to or higher than the recommended dose for patients months to 11 years of age. The safety of levocetirizine dihydrochloride mg once daily was evaluated in 243 pediatric patients to 12 years of age in two placebo-controlled clinical trials lasting and weeks. The safety of levocetirizine dihydrochloride 1.25 mg twice daily was evaluated in one 2-week clinical trial in 114 pediatric patients to years of age and the safety of levocetirizine dihydrochloride 1.25 mg once daily was evaluated in one 2-week clinical trial in 45 pediatric patients to 11 months of age [see Adverse Reactions (6.1)]. The effectiveness of levocetirizine dihydrochloride 1.25 mg once daily (6 months to years of age) and 2.5 mg once daily (6 to 11 years of age) for the treatment of the symptoms of perennial allergic rhinitis and chronic idiopathic urticaria is supported by the extrapolation of demonstrated efficacy of levocetirizine dihydrochloride 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 dihydrochloride to to 12 year old pediatric patients resulted in about 2-fold the systemic exposure (AUC) observed when mg of levocetirizine dihydrochloride 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. In population pharmacokinetics study the administration of 1.25 mg once daily in children months to years of age resulted in systemic exposure comparable to mg once daily in adults [see Dosage and Administration (2.2), Clinical Studies (14), and Clinical Pharmacology (12.3)]. 8.5 Geriatric Use. Clinical studies of levocetirizine dihydrochloride 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 dihydrochloride 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 oral solution.(5.1) Avoid concurrent use of alcohol or other central nervous system depressants with levocetirizine dihydrochloride oral solution. (5.1) Use with caution in patients with predisposing factors of urinary retention (e.g. spinal cord lesion, prostatic hyperplasia). Discontinue levocetirizine dihydrochloride oral solution 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. 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. Concurrent use of levocetirizine dihydrochloride 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. Levocetirizine dihydrochloride should be used with caution in patients with predisposing factors of urinary retention (e.g. spinal cord lesion, prostatic hyperplasia) as levocetirizine dihydrochloride may increase the risk of urinary retention. Discontinue levocetirizine dihydrochloride if urinary retention occurs.