NDC 0024-5803 Xyzal

Levocetirizine Dihydrochloride

NDC Product Code 0024-5803

NDC CODE: 0024-5803

Proprietary Name: Xyzal What is the Proprietary Name?
The proprietary name also known as the trade name is the name of the product chosen by the medication labeler for marketing purposes.

Non-Proprietary Name: Levocetirizine Dihydrochloride What is the Non-Proprietary Name?
The non-proprietary name is sometimes called the generic name. The generic name usually includes the active ingredient(s) of the product.

Drug Use Information

Drug Use Information
The drug use information is a summary and does NOT have all possible information about this product. This information does not assure that this product is safe, effective, or appropriate. This information is not individual medical advice and does not substitute for the advice of a health care professional. Always ask a health care professional for complete information about this product and your specific health needs.

  • Levocetirizine is an antihistamine used to relieve allergy symptoms such as watery eyes, runny nose, itching eyes/nose, and sneezing. It is also used to relieve itching and hives. It works by blocking a certain natural substance (histamine) that your body makes during an allergic reaction. Levocetirizine does not prevent hives or prevent/treat a serious allergic reaction (such as anaphylaxis). If your doctor has prescribed epinephrine to treat allergic reactions, always carry your epinephrine injector with you. Do not use levocetirizine in place of your epinephrine.

Product Characteristics

Color(s):
WHITE (C48325)
Shape: OVAL (C48345)
Size(s):
8 MM
Imprint(s):
Y;Y
Score: 2

NDC Code Structure

  • 0024 - Sanofi-aventis U.s. Llc

NDC 0024-5803-90

Package Description: 90 TABLET, FILM COATED in 1 BOTTLE

NDC Product Information

Xyzal with NDC 0024-5803 is a a human prescription drug product labeled by Sanofi-aventis U.s. Llc. The generic name of Xyzal is levocetirizine dihydrochloride. The product's dosage form is tablet, film coated and is administered via oral form.

Labeler Name: Sanofi-aventis U.s. Llc

Dosage Form: Tablet, Film Coated - A solid dosage form that contains medicinal substances with or without suitable diluents and is coated with a thin layer of a water-insoluble or water-soluble polymer.

Product Type: Human Prescription Drug What kind of product is this?
Indicates the type of product, such as Human Prescription Drug or Human Over the Counter Drug. This data element matches the “Document Type” field of the Structured Product Listing.

Xyzal Active Ingredient(s)

What is the Active Ingredient(s) List?
This is the active ingredient list. Each ingredient name is the preferred term of the UNII code submitted.

  • LEVOCETIRIZINE DIHYDROCHLORIDE 5 mg/1

Inactive Ingredient(s)

About the Inactive Ingredient(s)
The inactive ingredients are all the component of a medicinal product OTHER than the active ingredient(s). The acronym "UNII" stands for “Unique Ingredient Identifier” and is used to identify each inactive ingredient present in a product.

  • MICROCRYSTALLINE CELLULOSE (UNII: OP1R32D61U)
  • LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X)
  • SILICON DIOXIDE (UNII: ETJ7Z6XBU4)
  • MAGNESIUM STEARATE (UNII: 70097M6I30)
  • HYPROMELLOSE, UNSPECIFIED (UNII: 3NXW29V3WO)
  • TITANIUM DIOXIDE (UNII: 15FIX9V2JP)
  • POLYETHYLENE GLYCOL 400 (UNII: B697894SGQ)
  • FD&C RED NO. 40 (UNII: WZB9127XOA)
  • SHELLAC (UNII: 46N107B71O)

Administration Route(s)

What are the Administration Route(s)?
The translation of the route code submitted by the firm, indicating route of administration.

  • Oral - Administration to or by way of the mouth.
  • Oral - Administration to or by way of the mouth.

Pharmacological Class(es)

What is a Pharmacological Class?
These are the reported pharmacological class categories corresponding to the SubstanceNames listed above.

  • Histamine H1 Receptor Antagonists - [MoA] (Mechanism of Action)
  • Histamine-1 Receptor Antagonist - [EPC] (Established Pharmacologic Class)

Product Labeler Information

What is the Labeler Name?
Name of Company corresponding to the labeler code segment of the Product NDC.

Labeler Name: Sanofi-aventis U.s. Llc
Labeler Code: 0024
FDA Application Number: NDA022064 What is the FDA Application Number?
This corresponds to the NDA, ANDA, or BLA number reported by the labeler for products which have the corresponding Marketing Category designated. If the designated Marketing Category is OTC Monograph Final or OTC Monograph Not Final, then the Application number will be the CFR citation corresponding to the appropriate Monograph (e.g. “part 341”). For unapproved drugs, this field will be null.

Marketing Category: NDA - A product marketed under an approved New Drug Application. What is the Marketing Category?
Product types are broken down into several potential Marketing Categories, such as NDA/ANDA/BLA, OTC Monograph, or Unapproved Drug. One and only one Marketing Category may be chosen for a product, not all marketing categories are available to all product types. Currently, only final marketed product categories are included. The complete list of codes and translations can be found at www.fda.gov/edrls under Structured Product Labeling Resources.

Start Marketing Date: 07-24-2017 What is the Start Marketing Date?
This is the date that the labeler indicates was the start of its marketing of the drug product.

Listing Expiration Date: 12-31-2021 What is the Listing Expiration Date?
This is the date when the listing record will expire if not updated or certified by the product labeler.

Exclude Flag: N What is the NDC Exclude Flag?
This field indicates whether the product has been removed/excluded from the NDC Directory for failure to respond to FDA’s requests for correction to deficient or non-compliant submissions. Values = ‘Y’ or ‘N’.

* Please review the disclaimer below.

Xyzal Product Label Images

Xyzal Product Labeling Information

The product labeling information includes all published material associated to a drug. Product labeling documents include information like generic names, active ingredients, ingredient strength dosage, routes of administration, appearance, usage, warnings, inactive ingredients, etc.

Product Labeling Index

1.1 Perennial Allergic Rhinitis

XYZAL is indicated for the relief of symptoms associated with perennial allergic rhinitis in children 6 months to 2 years of age.

1.2 Chronic Idiopathic Urticaria

XYZAL is indicated for the treatment of the uncomplicated skin manifestations of chronic idiopathic urticaria in adults and children 6 months of age and older.

2 Dosage And Administration

XYZAL is available as 2.5 mg/5 mL (0.5 mg/mL) oral solution and as 5 mg breakable (scored) tablets, allowing for the administration of 2.5 mg, if needed. XYZAL can be taken without regard to food consumption.

Other

Children 6 months to 2 Years of AgeThe recommended initial dose of XYZAL 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 5 mg [see Clinical Pharmacology (12.3)].

Adults and Children 12 Years of Age and OlderThe recommended dose of XYZAL is 5 mg (1 tablet or 2 teaspoons [10 mL] oral solution) once daily in the evening. Some patients may be adequately controlled by 2.5 mg (1/2 tablet or 1 teaspoon [5 mL] oral solution) once daily in the evening.

Children 6 to 11 Years of AgeThe recommended dose of XYZAL is 2.5 mg (1/2 tablet or 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 5 mg is approximately twice that of adults [see Clinical Pharmacology (12.3)].

Children 6 months to 5 Years of AgeThe recommended initial dose of XYZAL 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 5 mg [see Clinical Pharmacology (12.3)].

  • Dose Adjustment for Renal and Hepatic ImpairmentIn adults and children 12 years of age and older with:Mild renal impairment (creatinine clearance [CLCR] = 50–80 mL/min): a dose of 2.5 mg once daily is recommended;Moderate renal impairment (CLCR = 30–50 mL/min): a dose of 2.5 mg once every other day is recommended;Severe renal impairment (CLCR = 10–30 mL/min): a dose of 2.5 mg twice weekly (administered once every 3–4 days) is recommended;End-stage renal disease patients (CLCR <10 mL/min) and patients undergoing hemodialysis should not receive XYZAL.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.

Adults and Adolescents 12 years of Age and OlderIn studies up to 6 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 XYZAL 2.5 mg and 5 mg groups, respectively, had at least one adverse event compared to 43% in the placebo group.In placebo-controlled trials of 1–6 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 XYZAL showed dose ordering between tested doses of 2.5, 5 and 10 mg and was the most common adverse reaction leading to discontinuation (0.5%).Table 1 lists adverse reactions that were reported in greater than or equal to 2% of subjects aged 12 years and older exposed to XYZAL 2.5 mg or 5 mg in eight placebo-controlled clinical trials and that were more common with XYZAL than placebo.Table 1: Adverse Reactions Reported in ≥2%Rounded to the closest unit percentage of Subjects Aged 12 Years and Older Exposed to XYZAL 2.5 mg or 5 mg Once Daily in Placebo-Controlled Clinical Trials 1–6 Weeks in DurationAdverse ReactionsXYZAL 2.5 mg(n = 421)XYZAL 5 mg(n = 1070)Placebo(n = 912)Somnolence22 (5%)61 (6%)16 (2%)Nasopharyngitis25 (6%)40 (4%)28 (3%)Fatigue5 (1%)46 (4%)20 (2%)Dry Mouth12 (3%)26 (2%)11 (1%)Pharyngitis10 (2%)12 (1%)9 (1%)Additional adverse reactions of medical significance observed at a higher incidence than in placebo in adults and adolescents aged 12 years and older exposed to XYZAL are syncope (0.2%) and weight increased (0.5%).

Pediatric Patients 6 to 12 Years of AgeA total of 243 pediatric patients 6 to 12 years of age received XYZAL 5 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 6 to 8 years of age, and 50% were Caucasian. Table 2 lists adverse reactions that were reported in greater than or equal to 2% of subjects aged 6 to 12 years exposed to XYZAL 5 mg in placebo-controlled clinical trials and that were more common with XYZAL than placebo.Table 2: Adverse Reactions Reported in ≥2%Rounded to the closest unit percentage of Subjects Aged 6–12 Years Exposed to XYZAL 5 mg Once Daily in Placebo-Controlled Clinical Trials 4 and 6 Weeks in DurationAdverse ReactionsXYZAL 5 mg (n = 243)Placebo(n = 240)Pyrexia10 (4%)5 (2%)Cough 8 (3%)2 (<1%)Somnolence7 (3%)1 (<1%)Epistaxis6 (2%)1 (<1%)

Pediatric Patients 1 to 5 Years of AgeA total of 114 pediatric patients 1 to 5 years of age received XYZAL 1.25 mg twice daily in a two week placebo-controlled double-blind safety trial. The mean age of the patients was 3.8 years, 32% were 1 to 2 years of age, 71% were Caucasian and 18% were Black. Table 3 lists adverse reactions that were reported in greater than or equal to 2% of subjects aged 1 to 5 years exposed to XYZAL 1.25 mg twice daily in the placebo-controlled safety trial and that were more common with XYZAL than placebo.Table 3: Adverse Reactions Reported in ≥2%Rounded to the closest unit percentage of Subjects Aged 1–5 Years Exposed to XYZAL 1.25 mg Twice Daily in a 2-Week Placebo-Controlled Clinical TrialAdverse ReactionsXYZAL 1.25 mg Twice Daily(n = 114)Placebo(n = 59)Pyrexia5 (4%)1 (2%)Diarrhea4 (4%)2 (3%)Vomiting4 (4%)2 (3%)Otitis Media3 (3%)0 (0%)

Pediatric Patients 6 to 11 Months of AgeA total of 45 pediatric patients 6 to 11 months of age received XYZAL 1.25 mg once daily in a two week placebo-controlled double-blind safety trial. The mean age of the patients was 9 months, 51% were Caucasian and 31% were Black. Adverse reactions that were reported in more than 1 subject (i.e. greater than or equal to 3% of subjects) aged 6 to 11 months exposed to XYZAL 1.25 mg once daily in the placebo-controlled safety trial and that were more common with XYZAL than placebo included diarrhea and constipation which were reported in 6 (13%) and 1 (4%) and 3 (7%) and 1 (4%) children in the XYZAL and placebo-treated groups, respectively.

Long-Term Clinical Trials ExperienceIn two controlled clinical trials, 428 patients (190 males and 238 females) aged 12 years and older were treated with XYZAL 5 mg once daily for 4 or 6 months. The patient characteristics and the safety profile were similar to that seen in the short-term studies. Ten (2.3%) patients treated with XYZAL discontinued because of somnolence, fatigue or asthenia compared to 2 (<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 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.

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

AbsorptionLevocetirizine 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 2 days. Peak concentrations are typically 270 ng/mL and 308 ng/mL following a single and a repeated 5 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 a high fat meal; therefore, levocetirizine can be administered with or without food.A dose of 5 mg (10 mL) of XYZAL oral solution is bioequivalent to a 5 mg dose of XYZAL tablets. Following oral administration of a 5 mg dose of XYZAL oral solution to healthy adult subjects, the mean peak plasma concentrations were achieved approximately 0.5 hour post dose.

DistributionThe mean plasma protein binding of levocetirizine in vitro ranged from 91 to 92%, independent of concentration in the range of 90–5000 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.

MetabolismThe 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.

EliminationThe plasma half-life in adult healthy subjects was about 8 to 9 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 a 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 StudiesIn 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 patientsData from a pediatric pharmacokinetic study with oral administration of a single dose of 5 mg levocetirizine in 14 children age 6 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 a cross-study comparison. The mean Cmax was 450 ng/mL, occurring at a 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 6 years of age. A retrospective population pharmacokinetic analysis was conducted in 323 subjects (181 children 1 to 5 years of age, 18 children 6 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 administration of 1.25 mg once daily to children 6 months to 5 years of age results in plasma concentrations similar to those of adults receiving 5 mg once daily.

Geriatric patientsLimited pharmacokinetic data are available in elderly subjects. Following once daily repeat oral administration of 30 mg levocetirizine for 6 days in 9 elderly subjects (65–74 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 XYZAL dose should be adjusted in accordance with renal function in elderly patients [see Dosage and Administration (2)].

GenderPharmacokinetic 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.

RaceThe 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 impairmentLevocetirizine 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 a standard 4-hour hemodialysis procedure was <10%.The dosage of XYZAL 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 impairmentXYZAL 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)].

Reproductive Toxicology StudiesIn 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 a 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 a mg/m2 basis).

Adults and Adolescents 12 Years of Age and OlderThe efficacy of XYZAL 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 4 weeks duration and two efficacy trials (one 6-week and one 6-month) in patients with perennial allergic rhinitis.These trials included a total of 1729 patients (752 males and 977 females) of whom 227 were adolescents 12 to 17 years of age. Efficacy was assessed using a total symptom score from patient recording of 4 symptoms (sneezing, rhinorrhea, nasal pruritus, and ocular pruritus) in three studies and 5 symptoms (sneezing, rhinorrhea, nasal pruritus, ocular pruritus, and nasal congestion) in one study. Patients recorded symptoms using a 0–3 categorical severity scale (0 = absent, 1 = mild, 2 = moderate, 3 = 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 4 weeks for perennial allergic rhinitis trials.The two dose-ranging trials were conducted to evaluate the efficacy of XYZAL 2.5, 5, and 10 mg once daily in the evening. These trials were 4 weeks in duration and included patients with perennial allergic rhinitis. In these trials, each of the three doses of XYZAL 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 ScoreTotal symptom score is the sum of individual symptoms of sneezing, rhinorrhea, nasal pruritus, and ocular pruritus as assessed by patients on a 0–3 categorical severity scale. in Allergic Rhinitis Dose-Ranging TrialsTreatmentNBaselineOn Treatment Adjusted MeanDifference from PlaceboEstimate95% CI p-value Perennial Allergic Rhinitis Trial – Reflective total symptom scoreXYZAL 2.5 mg1337.144.121.17(0.71, 1.63)<0.001XYZAL 5 mg1277.184.071.22(0.76, 1.69)<0.001XYZAL 10 mg1297.584.191.10(0.64, 1.57)<0.001Placebo1287.225.29One clinical trial evaluated the efficacy of XYZAL 5 mg once daily in the evening compared to placebo in patients with perennial allergic rhinitis over a 6-week treatment period. Another trial conducted over a 6-month treatment period assessed efficacy at 4 weeks. XYZAL 5 mg demonstrated a 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 ScoreTotal symptom score is the sum of individual symptoms of sneezing, rhinorrhea, nasal pruritus, and ocular pruritus as assessed by patients on a 0–3 categorical severity scale. in Allergic Rhinitis TrialsTreatmentNBaselineOn Treatment Adjusted MeanDifference from PlaceboEstimate95% CI p-value Perennial Allergic Rhinitis Trial – Reflective total symptom scoreXYZAL 5 mg1507.693.931.17(0.70, 1.64)<0.001Placebo1427.445.10Onset of action was evaluated in two environmental exposure unit studies in allergic rhinitis patients with a single dose of XYZAL 2.5 or 5 mg. XYZAL 5 mg was found to have an onset of action 1 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 1 day of dosing.

Pediatric Patients Less than 12 Years of AgeThere are no clinical efficacy trials with XYZAL 2.5 mg once daily in pediatric patients under 12 years of age, and no clinical efficacy trials with XYZAL 1.25 mg once daily in pediatric patients 6 months to 5 years of age. The clinical efficacy of XYZAL 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)].

Adult Patients 18 Years of Age and OlderThe efficacy of XYZAL 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 4 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 XYZAL 5 mg once daily in the evening. Efficacy was assessed based on patient recording of pruritus severity on a severity score of 0–3 (0 = none to 3 = 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 XYZAL 2.5, 5, and 10 mg once daily in the evening. In this trial, each of the three doses of XYZAL 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 XYZAL 5 mg once daily in the evening compared to placebo in patients with chronic idiopathic urticaria over a 4-week treatment period. XYZAL 5 mg demonstrated a 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 TrialsTreatmentNBaselineOn Treatment Adjusted MeanDifference from PlaceboEstimate95% CI p-value Dose-Ranging Trial – Reflective pruritus severity scoreXYZAL 2.5 mg692.081.020.82(0.58, 1.06)<0.001XYZAL 5 mg622.070.920.91(0.66, 1.16)<0.001XYZAL 10 mg552.040.731.11(0.85, 1.37)<0.001Placebo602.251.84Chronic Idiopathic Urticaria Trial – Reflective pruritus severity scoreXYZAL 5 mg802.070.940.62(0.38, 0.86)<0.001Placebo822.061.56

Pediatric PatientsThere are no clinical efficacy trials in pediatric patients with chronic idiopathic urticaria [see Use in Specific Populations (8.4)].

SomnolenceCaution patients against engaging in hazardous occupations requiring complete mental alertness, and motor coordination such as operating machinery or driving a motor vehicle after ingestion of XYZAL.

Concomitant Use of Alcohol and other Central Nervous System DepressantsInstruct patients to avoid concurrent use of XYZAL with alcohol or other central nervous system depressants because additional reduction in mental alertness may occur.

Dosing of XYZALDo not exceed the recommended daily dose in adults and adolescents 12 years of age and older of 5 mg once daily in the evening. In children 6 to 11 years of age the recommended dose is 2.5 mg once daily in the evening. In children 6 months to 5 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 XYZAL because of the increased risk of somnolence at higher doses.

Manufactured for:sanofi-aventis, U.S. LLCBridgewater, NJ 08807A SANOFI COMPANYXYZAL is a registered trademark of UCB BIOPHARMA SPRL.©2018 UCB, Inc. All rights reserved.

3 Dosage Forms And Strengths

XYZAL oral solution is a clear, colorless liquid containing 0.5 mg of levocetirizine dihydrochloride per mL.XYZAL tablets are white, film-coated, oval-shaped, scored, imprinted (with the letter Y in red color on both halves of the scored tablet) and contain 5 mg levocetirizine dihydrochloride.

4 Contraindications

The use of XYZAL is contraindicated in:

4.1 Patients With Known Hypersensitivity

Patients with known hypersensitivity to levocetirizine or any of the ingredients of XYZAL, 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 6 months to 11 years of age with impaired renal function

5.1 Somnolence

In clinical trials the occurrence of somnolence, fatigue, and asthenia has been reported in some patients under therapy with XYZAL. Patients should be cautioned against engaging in hazardous occupations requiring complete mental alertness, and motor coordination such as operating machinery or driving a motor vehicle after ingestion of XYZAL. Concurrent use of XYZAL 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 post marketing with XYZAL. XYZAL should be used with caution in patients with predisposing factors of urinary retention (e.g. spinal cord lesion, prostatic hyperplasia) as XYZAL may increase the risk of urinary retention. Discontinue XYZAL if urinary retention occurs.

6 Adverse Reactions

Use of XYZAL has been associated with somnolence, fatigue, asthenia, and urinary retention [see Warnings and Precautions (5)].

6.1 Clinical Trials Experience

The safety data described below reflect exposure to XYZAL in 2708 patients with allergic rhinitis or chronic idiopathic urticaria in 14 controlled clinical trials of 1 week to 6 months duration.The short-term (exposure up to 6 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 XYZAL 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 6 to 12 years of age) were treated with XYZAL 5 mg once daily for 4 to 6 weeks, one clinical trial in which 114 children (65 males and 49 females 1 to 5 years of age) with allergic rhinitis or chronic idiopathic urticaria were treated with XYZAL 1.25 mg twice daily for 2 weeks, and one clinical trial in which 45 children (28 males and 17 females 6 to 11 months of age) with symptoms of allergic rhinitis or chronic urticaria were treated with XYZAL 1.25 mg once daily for 2 weeks.The long-term (exposure of 4 or 6 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 XYZAL 5 mg once daily. Long term safety data are also available from an 18-month trial in 255 XYZAL-treated subjects 12–24 months of age.Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trial of another drug and may not reflect the rates observed in practice.

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 XYZAL. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.Cardiac disorders: palpitations, tachycardiaEar and labyrinth disorders: vertigoEye disorders: blurred vision, visual disturbancesGastrointestinal disorders: nausea, vomitingGeneral disorders and administration site conditions: edemaHepatobiliary disorders: hepatitisImmune system disorders: anaphylaxis and hypersensitivityMetabolism and nutrition disorders: increased appetiteMusculoskeletal, connective tissues, and bone disorders: arthralgia, myalgiaNervous system disorders: dizziness, dysgeusia, febrile seizure, movement disorders (including dystonia and oculogyric crisis), paraesthesia, seizure (reported in subjects with and without a known seizure disorder), tremorPsychiatric disorders: aggression and agitation, depression, hallucinations, insomnia, nightmare, suicidal ideationRenal and urinary disorders: dysuria, urinary retentionRespiratory, thoracic, and mediastinal disorders: dyspneaSkin and subcutaneous tissue disorders: angioedema, fixed drug eruption, pruritus, rash and urticariaBesides these reactions reported under treatment with XYZAL, 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 XYZAL.Cardiac disorders: severe hypotensionGastrointestinal disorders: cholestasisNervous system disorders: extrapyramidal symptoms, myoclonus, orofacial dyskinesia, ticPregnancy, puerperium and perinatal conditions: stillbirthRenal and urinary disorders: glomerulonephritisSkin and subcutaneous tissue disorders: acute generalized exanthematous pustulosis (AGEP); rebound pruritus - pruritus within a few days after discontinuation of cetirizine, usually after long-term use (e.g. months to years) of cetirizine.

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 a small decrease (~16%) in the clearance of cetirizine caused by a 400 mg dose of theophylline. It is possible that higher theophylline doses could have a greater effect.

7.2 Ritonavir

Ritonavir increased the plasma AUC of cetirizine by about 42% accompanied by an increase in half-life (53%) and a decrease in clearance (29%) of cetirizine. The disposition of ritonavir was not altered by concomitant cetirizine administration.

Teratogenic Effects

Teratogenic EffectsIn 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 a mg/m2 basis.

8.3 Nursing Mothers

No peri and postnatal 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 a 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 XYZAL in nursing mothers is not recommended.

8.4 Pediatric Use

The recommended dose of XYZAL for the treatment of the uncomplicated skin manifestations of chronic idiopathic urticaria in patients 6 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 XYZAL in patients 6 months to 2 years of age for the treatment of the symptoms of perennial allergic rhinitis and 6 months to 11 years of age with chronic idiopathic urticaria is based on cross-study comparisons of the systemic exposure of XYZAL in adults and pediatric patients and on the safety profile of XYZAL in both adult and pediatric patients at doses equal to or higher than the recommended dose for patients 6 months to 11 years of age.The safety of XYZAL 5 mg once daily was evaluated in 243 pediatric patients 6 to 12 years of age in two placebo-controlled clinical trials lasting 4 and 6 weeks. The safety of XYZAL 1.25 mg twice daily was evaluated in one 2-week clinical trial in 114 pediatric patients 1 to 5 years of age and the safety of XYZAL 1.25 mg once daily was evaluated in one 2-week clinical trial in 45 pediatric patients 6 to 11 months of age [see Adverse Reactions (6.1)].The effectiveness of XYZAL 1.25 mg once daily (6 months to 5 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 XYZAL 5 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 a 5 mg dose of XYZAL to 6 to 12 year old pediatric patients resulted in about 2-fold the systemic exposure (AUC) observed when 5 mg of XYZAL was administered to healthy adults. Therefore, in children 6 to 11 years of age the recommended dose of 2.5 mg once daily should not be exceeded. In a population pharmacokinetics study the administration of 1.25 mg once daily in children 6 months to 5 years of age resulted in systemic exposure comparable to 5 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 XYZAL 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

XYZAL 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)].

10 Overdosage

Overdosage has been reported with XYZAL.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 XYZAL. Should overdose occur, symptomatic or supportive treatment is recommended. XYZAL is not effectively removed by dialysis, and dialysis will be ineffective unless a 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 6 to 11 years of age, and approximately 180 times the maximum recommended daily oral dose in children 6 months to 5 years of age on a 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 6 to 11 years of age, and approximately 370 times the maximum recommended daily oral dose in children 6 months to 5 years of age on a mg/m2 basis).

11 Description

Levocetirizine dihydrochloride, the active component of XYZAL tablets and oral solution, 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 R enantiomer of cetirizine hydrochloride, a racemic compound with antihistaminic properties. The empirical formula of levocetirizine dihydrochloride is C21H25ClN2O3∙2HCl. The molecular weight is 461.82 and the chemical structure is shown below:Levocetirizine dihydrochloride is a white, crystalline powder and is water soluble.XYZAL 5 mg tablets are formulated as immediate release, white, film-coated, oval-shaped scored tablets for oral administration. The tablets are imprinted on both halves of the scored line with the letter Y in red (Opacode® Red). Inactive ingredients are: microcrystalline cellulose, lactose monohydrate, colloidal anhydrous silica, and magnesium stearate. The film coating contains hypromellose, titanium dioxide, and macrogol 400.XYZAL 0.5 mg/mL oral solution is formulated as an immediate release, clear, colorless liquid. Inactive ingredients are: sodium acetate trihydrate, glacial acetic acid, maltitol solution, glycerin, methylparaben, propylparaben, saccharin, flavoring (consisting of triacetin, natural & artificial flavors, dl-alpha-tocopherol), purified water.

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 a 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. 6 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 5 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 a dose of 5 mg inhibited the wheal and flare caused by intradermal injection of histamine in 14 pediatric subjects (aged 6 to 11 years) and the activity persisted for at least 24 hours. The clinical relevance of histamine wheal skin testing is unknown.A QT/QTc study using a single dose of 30 mg of levocetirizine did not demonstrate an effect on the QTc interval. While a 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.

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 a 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 6 to 11 years of age and approximately 15 times the maximum recommended daily oral dose in children 6 months to 5 years of age on a mg/m2 basis). In a 2-year carcinogenicity study in mice, cetirizine caused an increased incidence of benign hepatic tumors in males at a dietary dose of 16 mg/kg (approximately 6 times the maximum recommended daily oral dose in adults, approximately 4 times the maximum recommended daily oral dose in children 6 to 11 years of age, and approximately 6 times the maximum recommended daily oral dose in children 6 months to 5 years of age on a mg/m2 basis). No increased incidence of benign tumors was observed at a dietary dose of 4 mg/kg (approximately 2 times the maximum recommended daily oral dose in adults, equivalent to the maximum recommended daily oral dose in children 6 to 11 years of age and approximately 2 times the maximum recommended daily oral dose in children 6 months to 5 years of age on a mg/m2 basis). The clinical significance of these findings during long-term use of XYZAL 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 a 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 a mg/m2 basis).

16 How Supplied/Storage And Handling

XYZAL tablets are white, film-coated, oval-shaped, scored, imprinted (with the letter Y in red color on both halves of the scored tablet) and contain 5 mg levocetirizine dihydrochloride. They are supplied in unit of use HDPE bottles.90 Tablets (NDC 0024-5803-90)XYZAL oral solution is a clear, colorless liquid containing 0.5 mg of levocetirizine dihydrochloride per mL.Oral Solution in 5 oz polypropylene bottles (NDC 0024-5804-05)

Storage And Handling

StorageStore at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].

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