LEVOCETIRIZINE DIHYDROCHLORIDE (Generic for XYZAL)

General Administration Information
For storage information, see the specific product information within the How Supplied section.

Route-Specific Administration

Oral Administration
-Administer in the evening.
-May administer with or without food.
Oral Solid Formulations
-Tablets: May be split in half.

Oral Liquid Formulations
-Oral solution: Administer using a calibrated measuring device.

Similar to other low-sedating antihistamines, side effects from levocetirizine reported in placebo-controlled trials in adults and children aged 12 years and older include somnolence/drowsiness (5% to 6%, vs. 2% placebo) and fatigue (1% to 4%, vs. 2% placebo); somnolence/drowsiness (3% vs. less than 1% placebo) was also reported in clinical trials involving children aged 6 to 12 years. Dizziness, tremor, vertigo, arthralgia, and myalgia have been reported in post-marketing experience with levocetirizine (patient ages unspecified). Caution patients to avoid driving, riding a bike, or participating in other hazardous activities while taking this medication. The combined incidence of drowsiness, fatigue, and asthenia was 8.1% for levocetirizine versus 3.1% for placebo in clinical study. Discontinuation due to somnolence/drowsiness, fatigue, or asthenia occurred in 2.3% of patients vs. less than 1% in placebo during long-term clinical trials. Adverse reaction profiles are similar regardless of the indication being treated.

Adverse effects of the mouth, nose, and throat may occur during levocetirizine therapy. In placebo controlled trials of levocetirizine, side effects reported in >= 2% of levocetirizine-treated patients aged 12 years and older, and at a greater incidence than seen with placebo, include nasal congestion (4-6%) and xerostomia (2-3%). Pharyngitis occurred at a rate of 1-2%, which was similar to that see in the placebo group (1%). Cough (3% vs. < 1% placebo) and epistaxis (2% vs. < 1% placebo) have been reported in clinical trials involving children age 6 to 12 years. Cough (1.6% vs. 0.8%) was also reported in a study of the safety of levocetirizine in children age 12 to 24 months. Otitis media (3% vs. 0% placebo) was reported in children aged 1 to 5 years.

Although not common, cardiovascular adverse events have been reported during levocetirizine therapy. In placebo-controlled trials of levocetirizine in patients aged 12 years and older (which included adults), more patients experienced syncope (0.2%) with levocetirizine than with placebo. World-wide post-marketing experience includes reports of palpitations, sinus tachycardia, and edema among levocertirizine treated patients. Severe hypotension has been reported in the post-marketing experience with cetirizine; levocetirizine is the active enantiomer of cetirizine.

In placebo controlled trials of levocetirizine involving patients aged 12 years and older, more patients experienced weight gain (0.5%) with levocetirizine than with placebo. Increased appetite has been reported post-marketing reports.

Although no cause-effect relationship has been established, infection and signs and symptoms of infections have been reported in pediatric patients treated with levocetirizine. In 2 clinical studies, 1 with children 6 to 12 years and 1 with children 1 to 5 years of age, pyrexia (fever) occurred at the same incidence: 4% receiving levocetirizine vs. 2% receiving placebo. Cases of infection reported in more patients receiving levocetirizine than placebo include otitis media (3% vs. 0) in children age 1 to 5 years and pneumonia (1.6% vs. 0.8%) in children age 12 to 24 months. In pediatric patients aged 6 to 12 years, adverse reactions have been reported to be mild or moderate; discontinuation is uncommon.

Vomiting and diarrhea have been reported in children aged 1 to 5 years during clinical trials (4% vs. 3% placebo, incidence for both). In infants 6 to 11 months of age, diarrhea (13% vs. 4% placebo) and constipation (7% vs. 4% placebo) were reported. Levocetirizine has been reported to cause transient elevations in bilirubin and liver function tests (elevated hepatic enzymes) at an incidence of < 1%. These elevations did not require drug discontinuation. Post-marketing experience includes reports of dysgeusia, nausea, cholestasis, and hepatitis; causal relationships have not been determined.

Adverse events related to the central nervous system have been reported during levocetirizine therapy. In a study of the safety of levocetirizine in children 12-24 months of age, the following adverse events occurred more frequently with levocetirizine compared to placebo: agitation (0.4% vs. 0 with placebo), seizures (0.4% vs. 0), febrile seizures (2% vs. 0.4%), insomnia (1.2% vs. 0.8%), and nervousness (0.4% vs. 0). Such events were not reported in clinical trials of levocetirizine involving older patients; however, aggression, agitation, depression, hallucinations, paresthesias, movement disorders (including dystonic reaction and oculogyric crisis), and seizures have been reported in world-wide post-marketing experience (patient ages unspecified). Practitioners should also be aware that suicidal ideation, orofacial dyskinesia, tics, myoclonia, and extrapyramidal symptoms have been reported in the post-marketing experience with cetirizine, as levocetirizine is the active enantiomer of cetirizine.

Hypersensitivity reactions have been noted in post-marketing experience with levocetirizine, including the following rare but potentially serious allergic or dermatologic events: anaphylactoid reactions, angioneurotic edema (angioedema), dyspnea, acute generalized exanthematous pustulosis (AGEP), fixed drug eruption, pruritus, rash (unspecified), and urticaria. Rebound pruritus may occur within a few days after discontinuation of levocetirizine, usually after long-term use (i.e., months to years). If signs or symptoms of hypersensitivity occur, discontinue levocetirizine (use is contraindicated in patients with known hypersensitivity to levocetirizine or certirizine).

Levocetirizine is the active enantiomer of cetirizine; thus, practitioners should be aware of post-marketing reports of serious adverse reactions with cetirizine. Post-marketing reports have shown the following rare but potentially serious adverse reactions in clinical use of cetirizine: hemolytic anemia, stillbirth (fetal demise), and thrombocytopenia. This list is not inclusive.

Renal adverse events may occur during levocetirizine therapy. In post-marketing experience, dysuria and urinary retention have been reported with levocetirizine use and glomerulonephritis with cetirizine use; causal relationships have not been established. Dosage adjustment is recommended in patients with renal impairment.

Visual impairment may occur during levocetirizine therapy. Both unspecified visual disturbance and blurred vision have been reported with post-marketing use of levocetirizine; causal relationships have not been established.

Levocetirizine is contraindicated for use in patients with a known hypersensitivity to the drug or to any of the formulation components or who have known cetirizine hypersensitivity. Though not listed in the levocetirizine product labeling, some experts recommended avoiding levocetirizine use in patients who have known hydroxyzine hypersensitivity. Cetirizine is the active metabolite of hydroxyzine and a cross-sensitivity may occur.

Levocetirizine is contraindicated for use in pediatric patients less than 12 years of age with any degree of renal impairment and in patients of any age with end stage renal disease/renal failure (CrCl less than 10 mL/minute) and those undergoing dialysis. Dosage adjustments are required for patients greater than 12 years of age with mild (CrCl 50 to 80 mL/minute), moderate (CrCl 30 to 50 mL/minute), or severe renal impairment (CrCl 10 to 30 mL/minute). Renal excretion is the primary route of levocetirizine elimination and renal clearance of the drug correlates with creatinine clearance.

Although levocetirizine causes less sedation than first-generation antihistamines, somnolence, fatigue, and asthenia have been reported by some patients. Patients receiving cetirizine should not perform activities requiring coordination and concentration, such as gymnastics, riding a bicycle, or for older adolescents, operation of vehicles, until they are aware of how this medication affects them. Because the effects of CNS depressants may be additive with antihistamines, counsel adolescents who could be at risk for ethanol intoxication to avoid the use of alcohol while taking levocetirizine.

Use levocetirizine with caution in patients with predisposing factors for urinary retention (e.g. spinal cord lesion, urethral stricture). Urinary retention has been reported with levocetirizine use and may be exacerbated by the drug.

Description: Levocetirizine, the R-enantiomer of cetirizine, is a selective piperazine H1-receptor antagonist. Studies have shown that the antihistaminic effects of racemic cetirizine reside in the R-enantiomer, levocetirizine, and not the S-enantiomer, dextrocetirizine. Levocetirizine is effective in the treatment of seasonal allergic rhinitis, perennial allergic rhinitis, and chronic spontaneous urticaria. Levocetirizine has been used off-label for the symptomatic relief of atopic dermatitis in pediatric patients. Based on results of in vitro studies, levocetirizine has demonstrated a 2-fold and 30-fold greater affinity for H1-receptors compared to cetirizine and dextrocetirizine, respectively. Levocetirizine and cetirizine have been found to have similar efficacy in the inhibition of histamine-induced wheal response, flare response, and nasal resistance. In 1 study, cetirizine demonstrated a longer itch response in patients with chronic spontaneous urticaria when compared to levocetirizine. Levocetirizine was found to be superior in suppression of histamine-induced skin reactions when compared to loratadine and desloratadine. Levocetirizine is FDA-approved for prescription use in infants as young as 6 months. In January 2017, levocetirizine 5 mg tablets were approved for non-prescription (OTC) use in children 6 years of age and older and the 0.5 mg/mL oral solution was approved OTC for children 2 years of age and older.

For the management of symptoms of seasonal allergies or perennial allergies, including allergic rhinitis:
Oral dosage (solution):
Infants and Children 6 months to 5 years: 1.25 mg PO once daily in the evening. Levocetirizine is FDA-approved for use in children 2 years of age and older for seasonal allergic rhinitis and for infants and children 6 months and older for perennial allergic rhinitis. The nonprescription (OTC) solution is labeled only for use in children 2 years and older.
Children 6 to 11 years: 2.5 mg PO once daily in the evening. In some clinical studies, children 6 to 12 years received 5 mg PO once daily; however, the FDA-approved product labeling warns against exceeding 2.5 mg/day because systemic exposure after a 5 mg dose is approximately twice that of adult patients.
Children and Adolescents 12 to 17 years: 5 mg PO once daily in the evening. Some patients may experience adequate symptom control with 2.5 mg PO once daily.
Oral dosage (tablet):
Children 6 to 11 years: 2.5 mg PO once daily in the evening. In some clinical studies, children 6 to 12 years received 5 mg PO once daily; however, the FDA-approved product labeling warns against exceeding 2.5 mg/day because systemic exposure after a 5 mg dose is approximately twice that of adult patients.
Children and Adolescents 12 to 17 years: 5 mg PO once daily in the evening. Some patients may experience adequate symptom control with 2.5 mg PO once daily.

For the treatment of uncomplicated skin manifestations of chronic spontaneous urticaria:
Oral dosage (oral solution):
Infants and Children 6 months to 5 years: 1.25 mg PO once daily in the evening.
Children 6 to 11 years: 2.5 mg PO once daily in the evening.
Children and Adolescents 12 years and older: 5 mg PO once daily in the evening. Some patients may experience adequate symptom control with 2.5 mg PO once daily.
Oral dosage (tablet):
Children 6 to 11 years: 2.5 mg PO once daily in the evening.
Children and Adolescents 12 years and older: 5 mg PO once daily in the evening. Some patients may experience adequate symptom control with 2.5 mg PO once daily.

For the symptomatic treatment of atopic dermatitis*:
Oral dosage (oral solution):
Children 1 to 2 years: 0.125 mg/kg/dose PO twice daily. Total daily dosage range from clinical studies: 2.83 to 3.83 mg/day.

Maximum Dosage Limits:
-Neonates
Safety and efficacy have not been established.
-Infants
Less than 6 months: Safety and efficacy have not been established.
6 to 11 months: 1.25 mg/day PO.
-Children
1 to 2 years: 1.25 mg/day PO; up to 0.125 mg/kg/dose PO twice daily has been used off-label for atopic dermatitis.
3 to 5 years: 1.25 mg/day PO.
6 to 11 years: 2.5 mg/day PO.
12 years: 5 mg/day PO.
-Adolescents
5 mg/day PO.

Patients with Hepatic Impairment Dosing
No dosage adjustment is needed for hepatic impairment.

Patients with Renal Impairment Dosing
According to the FDA-approved product label, the use of levocetirizine in children less than 12 years of age with any renal impairment is contraindicated. For patients 12 years and older, the following dosage adjustments are recommended:
CrCl 50 to 80 mL/minute: 2.5 mg PO once daily.
CrCl 30 to 50 mL/minute: 2.5 mg PO once every other day.
CrCl 10 to 30 mL/minute: 2.5 mg PO twice a week; administered every 3 to 4 days.
CrCl less than 10 mL/minute: Use is contraindicated.

Hemodialysis
Use of levocetirizine in patients undergoing hemodialysis is contraindicated.

*non-FDA-approved indication

Monograph content under development

Mechanism of Action: Levocetirizine is highly selective for histamine H1-receptors. Unlike cromolyn and nedocromil which block histamine release, H1-antagonists compete with free histamine for binding at H1-receptor sites. This competitive antagonism blocks the effects of histamine on H1-receptors in the GI tract, uterus, large blood vessels, and bronchial smooth muscle. Blockade of H1-receptors also suppresses the formation of edema, flare, and pruritus that result from histaminic activity. In in vitro studies, levocetirizine has a 2-fold higher affinity for the H1-receptors than cetirizine. Levocetirizine has a lower incidence of sedation compared to older antihistamines (e.g., diphenhydramine).

In patients with allergic rhinitis, the inflammatory response plays a prominent role in the development of nasal obstruction and involves a number of mediators. Initial release of histamine from mast cells is followed by late-phase reactions involving a number of other cells, such as fibroblasts, epithelial cells, neutrophils, eosinophils (especially in conditions with raised IgE levels), macrophages, platelets, and lymphocytes. Cell adhesion can also be part of the inflammatory process. Levocetirizine has demonstrated anti-inflammatory effects in both in vitro and in vivo studies. The anti-inflammatory action appears to be related to a reduction in eosinophils, neutrophils, interleukin-4 and interleukin-8.

Pharmacokinetics: Levocetirizine is administered orally. Levocetirizine is 91-92% protein bound. The mean volume of distribution is approximately 0.4 L/kg in both pediatric and adult patients. Only 14% of levocetirizine undergoes metabolism via aromatic oxidation, N-dealkylation, O-dealkylation, and taurine conjugation; the remaining 86% is excreted unchanged. The elimination half-life in healthy adults is approximately 8-9 hours and is somewhat shorter in pediatric patients. Urinary excretion accounts for 85.4% of a dose and the feces for 12.9%. Renal clearance correlates with creatinine clearance; levocetirizine is excreted by both glomerular filtration and active tubular secretion.

Affected cytochrome P450 isoenzymes: CYP3A4
CYP3A4 contributes to the metabolism of levocetirizine; however, clinically significant drug interactions are not expected. Only 14% of levocetirizine is metabolized via aromatic oxidation, N-dealkylation, O-dealkylation, and taurine conjugation. The CYP3A4 isoenzyme is responsible for dealkylation; the enzymes responsible for aromatic oxidation have not fully been elucidated. In vitro studies have demonstrated that levocetirizine does not inhibit CYP1A2, 2C9, 2C19, 2A1, 2D6, 2E1, or 3A4. In addition, levocetirizine does not induce CYP1A2, 2C9, or 3A4. Formal drug interaction studies with levocetirizine have not been performed; data have been extrapolated from cetirizine studies.


-Route-Specific Pharmacokinetics
Oral Route
The oral tablet and oral solution are bioequivalent. Levocetirizine is rapidly absorbed from the GI tract with peak plasma concentrations reached in approximately 0.5 to 0.9 hours after administration. Levocetirizine may be administered with or without food. Although food does not affect the extent of levocetirizine exposure (AUC), the rate of absorption of the tablets may be decreased and peak plasma concentrations reduced by 36% when administered with a high fat meal.


-Special Populations
Pediatrics
Infants and Children < 6 years
In a pharmacokinetic study, 15 children (12-24 months of age) suffering from recurrent cough and other allergy-related symptoms received levocetirizine 0.125 mg/kg/dose PO twice daily for 90 days. The following mean pharmacokinetic parameters were calculated: Tmax = 1 hour, Vd = 0.37 L/kg, and t1/2 = 4 hours. Pharmacokinetic parameters of children < 6 years were calculated from a retrospective population pharmacokinetic analysis that included 324 subjects (181 children aged 1 to 5 years, 19 children 6 to 11 years, and 124 adults 18 to 55 years). Single or multiple doses ranging from 1.25 to 30 mg levocetirizine were administered; resultant data indicate that children aged 6 months to 5 years who receive 1.25 mg daily have drug plasma concentrations similar to those of adults who receive 5 mg daily.

Children >= 6 years
In a single-dose pharmacokinetic study, 14 children (6-11 years of age) with mild allergic rhinitis received levocetirizine 5 mg PO. The following mean pharmacokinetic parameters were calculated: Tmax = 1.2 +/- 0.2 hours, Vd = 0.4 +/- 0.02 L/kg, CL = 0.82 +/- 0.05 ml/kg/min (30% greater weight-normalized apparent body clearance than that of adults), and t1/2 = 5.7 +/- 0.2 hours (24% reduction when compared to adults). The Cmax and AUC values were about 2-fold greater than those reported in healthy adult subjects who also received a 5 mg dose in a cross-study comparison.

Hepatic Impairment
The effects of hepatic impairment on levocetirizine have not been studied. Non-renal clearance accounts for a minor portion of levocetirizine elimination; therefore, hepatic impairment is unlikely to result in significant change in levocetirizine clearance.

Renal Impairment
In patients with mild, moderate, and severe renal impairment, the levocetirizine AUC is increased by 1.8-, 3.2-, and 4.3-fold, respectively, and the half-life is increased by 1.4-, 2-, and 2.9-fold. In patients with renal failure (CrCl < 10 ml/min), the AUC and half-life is increased by 5.7- and 4-fold, respectively. Dialysis removes less than 10% of levocetirizine from the blood. Dosage adjustments are necessary in adolescent and adult patients with mild, moderate, or severe renal impairment; due to a lack of data in infants and children, use is not recommended in these patients if renal impairment is present. Levocetirizine should not be administered to patients with renal failure (CrCl < 10 ml/min), those on dialysis, and children < 12 years with any degree of renal impairment.