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Introduction

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Generic Name(s):

Associated Monographs

Levocetirizine, the R -enantiomer of cetirizine, is a second generation antihistamine.

Uses

[Section Outline]

Levocetirizine, the R -enantiomer of cetirizine, is used for the management of allergic rhinitis and chronic idiopathic urticaria. For additional information on these and other uses of antihistamines, see Uses in the Antihistamines General Statement 4:00.

Allergic Rhinitis !!navigator!!

Levocetirizine is used to provide symptomatic (nasal and nonnasal) relief of seasonal (e.g., hay fever) allergic rhinitis. Levocetirizine also is used to provide symptomatic (nasal and nonnasal) relief of perennial (nonseasonal) allergic rhinitis.

Antihistamines are not curative and merely provide palliative therapy; since seasonal allergic rhinitis may be a chronic, recurrent condition, successful therapy often may require long-term, intermittent use of these drugs. In the treatment of seasonal allergic rhinitis, antihistamines are more likely to be beneficial when therapy is initiated at the beginning of the hay fever season when pollen counts are low. Antihistamines are less likely to be effective when pollen counts are high, when pollen exposure is prolonged, and when nasal congestion is prominent. Chronic nasal congestion and headache caused by edema of the paranasal sinus mucosa often are refractory to antihistamine therapy. Antihistamines generally are not effective in relieving symptoms of nasal obstruction.

Safety and efficacy of levocetirizine in the management of seasonal allergic rhinitis were established in several randomized, double-blind, placebo-controlled studies of 2 weeks' duration in patients 12 years of age and older with seasonal allergic rhinitis. In these studies, treatment with levocetirizine dihydrochloride 5 mg once daily in the evening was more effective than placebo in reducing nasal (e.g., rhinorrhea, sneezing, nasal itching) and nonnasal (e.g., ocular itching) symptoms (as assessed by reduction in total symptom scores) in patients with seasonal allergic rhinitis. Limited data from several short-term (2 days' duration), comparative, allergen challenge chamber studies indicate that levocetirizine dihydrochloride (5 mg daily) may be more effective than desloratadine (5 mg daily), fexofenadine hydrochloride (120 mg daily), or montelukast (10 mg daily) in reducing nasal (e.g., rhinorrhea, sneezing, nasal itching) and nonnasal (e.g., ocular itching, ocular tearing) symptoms (as assessed by reduction in major symptom complex scores) of seasonal allergic rhinitis. However, well-controlled, long-term studies are required to fully determine levocetirizine's clinical profile relative to other agents used for the management of seasonal allergic rhinitis.

Safety and efficacy of levocetirizine in the management of perennial (nonseasonal) allergic rhinitis were established in several randomized, double-blind, placebo-controlled studies of 4 weeks to 6 months' duration in patients 12 years of age and older with perennial allergic rhinitis. In these studies, treatment with levocetirizine dihydrochloride 5 mg daily in the evening was more effective than placebo in reducing nasal (e.g., rhinorrhea, sneezing, nasal itching) and nonnasal (e.g., ocular itching) symptoms (as assessed by reduction in total symptom scores) of perennial allergic rhinitis; treatment with levocetirizine also was associated with an improvement in health-related quality of life and health status compared with placebo. Data from a randomized study in a limited number of adult patients with persistent (more than 4 days per week and for more than 4 weeks) allergic rhinitis indicate that levocetirizine dihydrochloride 5 mg daily may be slightly more effective than montelukast 10 mg daily in reducing nasal and nonnasal symptoms (as assessed by reduction in total symptom scores). Results of this study also indicate that combination therapy with levocetirizine dihydrochloride (5 mg daily) and montelukast (10 mg daily) is more effective than montelukast monotherapy (but not levocetirizine monotherapy) in reducing nasal and nonnasal symptoms. Limited data indicate that levocetirizine also may be effective in improving respiratory (e.g., upper/lower airway) and nonrespiratory (e.g., ocular itching) symptoms in adult patients with persistent allergic rhinitis who have concomitant mild intermittent asthma.

Safety and efficacy of levocetirizine in the management of seasonal or perennial allergic rhinitis in children 6 years of age and older have been evaluated in several randomized, double-blind, placebo-controlled studies of 4-6 weeks' duration in patients 6-12 years of age with seasonal or perennial allergic rhinitis. In these studies, treatment with levocetirizine dihydrochloride 5 mg daily was more effective than placebo in reducing nasal (e.g., rhinorrhea, sneezing, nasal itching) and nonnasal (e.g., ocular itching) symptoms (as assessed by reduction in total symptom scores) in pediatric patients with seasonal or perennial allergic rhinitis. Efficacy of levocetirizine dihydrochloride 2.5 mg once daily (in pediatric patients 6-11 years of age) and levocetirizine dihydrochloride 1.25 mg once daily (in pediatric patients 6 months to 5 years of age) for the management of seasonal or perennial allergic rhinitis is based on extrapolation of the demonstrated efficacy of the 5-mg daily dosage in pediatric patients 12 years of age and older and on pharmacokinetic comparisons in adults and children.

In clinical studies, symptomatic (i.e., nasal and nonnasal) improvement was observed as early as 1 day after initiation of levocetirizine therapy and maintained over the 24-hour dosage interval and throughout the entire treatment period.

Chronic Idiopathic Urticaria !!navigator!!

Levocetirizine is used for the symptomatic treatment of uncomplicated skin manifestations of chronic idiopathic urticaria. Safety and efficacy of levocetirizine in the management of chronic idiopathic urticaria were established in several randomized, double-blind, placebo-controlled studies of 4-6 weeks' duration in adult patients with chronic idiopathic urticaria. In these studies, treatment with levocetirizine dihydrochloride 5 mg once daily in the evening was more effective than placebo in decreasing the severity and duration of pruritus, the number and size of wheals, and the number of urticarial episodes. Treatment with levocetirizine also was associated with an improvement in quality of life, a lower rate of work absenteeism, and higher productivity at work compared with placebo. Limited data from a 4-week randomized, comparative study indicate that levocetirizine dihydrochloride (5 mg daily) may be more effective than desloratadine (5 mg daily) in decreasing the severity and duration of pruritus, but not the number and size of wheals, in patients with chronic idiopathic urticaria; the clinical relevance of these findings has not been fully established.

Safety and efficacy of levocetirizine in the management of chronic idiopathic urticaria have not been established in pediatric patients. Efficacy of levocetirizine dihydrochloride 2.5 mg once daily (in pediatric patients 6-11 years of age) and levocetirizine dihydrochloride 1.25 mg once daily (in pediatric patients 6 months to 5 years of age) for the management of chronic idiopathic urticaria is based on extrapolation of the demonstrated efficacy of the 5-mg daily dosage in adults and/or on pharmacokinetic comparisons in adults and children.

In clinical studies, symptomatic improvement was observed as early as 1 day after initiation of levocetirizine therapy and maintained throughout the entire treatment period.

Dosage and Administration

[Section Outline]

Administration !!navigator!!

Levocetirizine dihydrochloride is administered orally once daily in the evening without regard to meals.

Levocetirizine tablets are scored and can be broken in half (each half providing a dose of 2.5 mg).

Dosage !!navigator!!

The manufacturer states that a 5-mg dose of levocetirizine dihydrochloride administered as the commercially available oral solution containing 2.5 mg/5 mL is bioequivalent to a 5-mg tablet.

Allergic Rhinitis

For symptomatic relief of seasonal allergic rhinitis, the recommended dosage of levocetirizine dihydrochloride in adults and children 12 years of age and older is 5 mg once daily; alternatively, a dosage of 2.5 mg once daily may be adequate for some patients. The recommended dosage in children 6-11 years of age is 2.5 mg once daily; the recommended dosage in children 2-5 years of age is 1.25 mg once daily (as an oral solution). (See Pediatric Use under Warnings/Precautions: Specific Populations, in Cautions.) The manufacturer states that recommended dosages of levocetirizine should not be exceeded because higher dosages may be associated with an increased risk of somnolence.

For symptomatic relief of perennial (nonseasonal) allergic rhinitis, the recommended dosage of levocetirizine dihydrochloride in adults and children 12 years of age and older is 5 mg once daily; alternatively, a dosage of 2.5 mg once daily may be adequate for some patients. The recommended dosage in children 6-11 years of age is 2.5 mg once daily; the recommended dosage in children 6 months to 5 years of age is 1.25 mg once daily (as an oral solution). (See Pediatric Use under Warnings/Precautions: Specific Populations, in Cautions.)The manufacturer states that recommended dosages of levocetirizine should not be exceeded because higher dosages may be associated with an increased risk of somnolence.

Chronic Idiopathic Urticaria

For symptomatic relief of chronic idiopathic urticaria, the recommended dosage of levocetirizine dihydrochloride in adults and children 12 years of age and older is 5 mg once daily; alternatively, a dosage of 2.5 mg once daily may be adequate for some patients. The recommended dosage in children 6-11 years of age is 2.5 mg once daily; the recommended dosage in children 6 months to 5 years of age is 1.25 mg once daily (as an oral solution). (See Pediatric Use under Warnings/Precautions: Specific Populations, in Cautions and also see Advice to Patients.) The manufacturer states that recommended dosages of levocetirizine should not be exceeded because higher dosages may be associated with an increased risk of somnolence.

Special Populations !!navigator!!

Dosage of levocetirizine should be selected with caution in geriatric patients (usually starting at the low end of the dosage range) because of the greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy. (See Geriatric Use under Warnings/Precautions: Specific Populations, in Cautions.)

No dosage adjustment is required in patients with hepatic impairment.

Use of levocetirizine is contraindicated in children 6 months to 11 years of age with renal impairment. (See Cautions: Contraindications.) In adults and children 12 years of age and older with renal impairment, dosage of levocetirizine should be selected based on the degree of renal impairment. (See Table 1.)

Table 1. Dosage for Symptomatic Treatment of Allergic Rhinitis and Chronic Idiopathic Urticaria in Adults and Children 12 Years of Age and Older with Renal Impairment

Creatinine clearance (Clcr) (mL/minute)

Dosage

50-80

2.5 mg once daily

30-50

2.5 mg every other day

10-30

2.5 mg twice weekly (administered every 3-4 days)

<10 (or undergoing hemodialysis)

Use contraindicated

Cautions

[Section Outline]

Contraindications !!navigator!!

Known hypersensitivity (e.g., urticaria, anaphylaxis) to levocetirizine or any ingredient in the formulation, or to cetirizine.

Adults and children 12 years of age and older with end-stage renal disease (creatinine clearance less than 10 mL/minute) or undergoing hemodialysis.

Pediatric patients 6 months to 11 years of age with renal impairment.

Warnings/Precautions !!navigator!!

CNS Effects

Somnolence, fatigue, and asthenia have been reported in patients receiving levocetirizine in clinical studies. Patients should be advised to avoid performing hazardous activities requiring complete mental alertness or physical coordination (e.g., operating machinery, driving a motor vehicle) following use of levocetirizine. (See Advice to Patients.) Concomitant use of levocetirizine with alcohol or other CNS depressants should be avoided.

Specific Populations

Pregnancy

Category B. (See Users Guide.)

Lactation

Levocetirizine is expected to be distributed into milk (since cetirizine is distributed into milk). Use is not recommended in nursing women.

Pediatric Use

Safety of levocetirizine has not been established in children younger than 6 months of age.

Efficacy of levocetirizine dihydrochloride 1.25 mg once daily (in pediatric patients 6 months to 5 years of age) and levocetirizine dihydrochloride 2.5 mg once daily (in pediatric patients 6-11 years of age) for the management of allergic rhinitis is based on extrapolation of the demonstrated efficacy of the 5-mg daily dosage in pediatric patients 12 years of age and older and on pharmacokinetic comparisons in adults and children.

Efficacy of levocetirizine dihydrochloride 1.25 mg once daily (in pediatric patients 6 months to 5 years of age), levocetirizine dihydrochloride 2.5 mg once daily (in pediatric patients 6-11 years of age), and levocetirizine dihydrochloride 5 mg once daily (in pediatric patients 12-17 years of age) for the management of chronic idiopathic urticaria is based on extrapolation of the demonstrated efficacy of the 5-mg daily dosage in adults and/or on pharmacokinetic comparisons in adults and children.

A cross-study comparison of pharmacokinetic data indicate that systemic exposure (i.e., peak plasma concentrations, area under the plasma concentration-time curve [AUC]) to levocetirizine was approximately twofold higher in pediatric patients 6-11 years of age with seasonal allergic rhinitis receiving a single 5-mg dose compared with that reported in adults receiving the same dose. Data from a retrospective population pharmacokinetic analysis indicate that administration of levocetirizine dihydrochloride 1.25 mg once daily in children 6 months to 5 years of age results in plasma levocetirizine concentrations that are comparable to those observed in adults receiving the drug at a dosage of 5 mg once daily.

Overdosage and toxicity (including death) have been reported in children younger than 2 years of age receiving nonprescription (over-the-counter, OTC) preparations containing antihistamines, cough suppressants, expectorants, and nasal decongestants alone or in combination for relief of symptoms of upper respiratory tract infection. Clinicians should ask caregivers about use of nonprescription cough and cold preparations to avoid overdosage.

Geriatric Use

Experience from clinical trials in patients 65 years of age and older is insufficient to determine whether geriatric patients respond differently than younger adults. Other reported clinical experience has not identified differences in responses between geriatric and younger patients. Dosage of levocetirizine generally should be selected with caution in geriatric patients because of the greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy. (See Dosage and Administration: Special Populations.) Periodic monitoring of renal function may be useful.

Hepatic Impairment

The pharmacokinetics of levocetirizine have not been evaluated in patients with hepatic impairment. However, because levocetirizine is mainly excreted unchanged in the kidneys, it is unlikely that clearance of the drug is substantially decreased in patients with hepatic impairment. Dosage adjustment is not necessary in such patients.

Renal Impairment

The AUC of levocetirizine is increased by 1.8-, 3.2-, or 4.3-fold in patients with mild, moderate, or severe renal impairment, respectively, and by 5.7-fold in patients with end-stage renal disease, compared with individuals without renal impairment. The half-life of the drug is increased by 1.4-, 2-, 2.9-, or fourfold, respectively, in such patients. Total body clearance of levocetirizine correlates with creatinine clearance and progressively decreases based on the severity of renal impairment. Dosage adjustment is necessary based on the degree of renal impairment. (See Dosage and Administration: Special Populations and also see Cautions: Contraindications.)

Less than 10% of an administered dose of levocetirizine is removed during a standard 4-hour hemodialysis procedure.

Common Adverse Effects !!navigator!!

Adverse effects reported in 2% or more of patients 12 years of age and older receiving levocetirizine dihydrochloride (2.5 or 5 mg daily) in clinical trials and occurring more frequently than placebo include somnolence, nasopharyngitis, fatigue, dry mouth, and pharyngitis.

Adverse effects reported in 2% or more of pediatric patients 6-12 years of age receiving levocetirizine dihydrochloride (5 mg daily) in clinical trials and occurring more frequently than placebo include pyrexia, cough, somnolence, and epistaxis.

Adverse effects reported in 2% or more of pediatric patients 1-5 years of age receiving levocetirizine dihydrochloride (1.25 mg twice daily) in a safety trial and occurring more frequently than with placebo include pyrexia, diarrhea, vomiting, and otitis media.

Adverse effects reported in 3% or more of pediatric patients 6-11 months of age receiving levocetirizine dihydrochloride (1.25 mg once daily) in a safety trial and occurring more frequently than placebo include diarrhea and constipation.

Drug Interactions

[Section Outline]

No formal drug interaction studies have been performed with levocetirizine to date; studies have been performed with racemic cetirizine.

Levocetirizine does not inhibit cytochrome P-450 (CYP) isoenzymes 1A2, 2C9, 2C19, 2A1, 2D6, 2E1, or 3A4. The drug does not induce uridine diphosphate-glucuronosyltransferase (UGT) 1A or CYP isoenzymes 1A2, 2C9, or 3A4. The manufacturer states that levocetirizine is unlikely to produce or be subject to pharmacokinetic interactions associated with metabolic enzyme systems.

Azithromycin !!navigator!!

No clinically important changes in ECG parameters were observed following concomitant administration of azithromycin with cetirizine, and no clinically important interactions have been reported following such concomitant use.

CNS Depressants (e.g., Alcohol) !!navigator!!

Possible additive adverse CNS effects. Concomitant use should be avoided.

Cimetidine !!navigator!!

No pharmacokinetic interactions were observed with concomitant administration of cimetidine and cetirizine.

Erythromycin !!navigator!!

No clinically important changes in ECG parameters were observed following concomitant administration of erythromycin with cetirizine, and no clinically important interactions have been reported following such concomitant use.

Ketoconazole !!navigator!!

Prolongation of the QTc interval (with an increase of 17.4 msec) was observed following concomitant administration of ketoconazole with cetirizine; no other clinically important interactions have been reported following such concomitant use. This interaction is not considered clinically important.

Pseudoephedrine !!navigator!!

No pharmacokinetic interactions have been observed with concomitant administration of pseudoephedrine and cetirizine.

Ritonavir !!navigator!!

Concomitant administration of cetirizine and ritonavir resulted in increased area under the plasma concentration-time curve (AUC) (42%), increased half-life (53%), and decreased clearance (29%) of cetirizine; the disposition of ritonavir was not altered.

Theophylline !!navigator!!

Concomitant administration of cetirizine with theophylline resulted in decreased clearance (16%) of cetirizine; the disposition of theophylline was not altered.

Other Information

[Section Outline]

Pharmacokinetics

Absorption !!navigator!!

Bioavailability

Rapidly and extensively absorbed following oral administration, with peak plasma concentration usually attained in 0.9 hour (tablets) or 0.5 hour (oral solution).

Onset

Antihistaminic effects occur within 1 hour. Symptomatic improvement observed as early as 1 day after initiation of therapy for allergic rhinitis or chronic idiopathic urticaria.

Duration

Antihistaminic effects persist for at least 24 hours.

Food

A high-fat meal reduces peak plasma concentration by about 36% and delays time to peak plasma concentration by about 1.25 hours, but does not affect AUC.

Special Populations

In patients with renal impairment, AUC is increased by 1.8-, 3.2-, or 4.3-fold in those with mild, moderate, or severe impairment, respectively; AUC is increased by 5.7-fold in those with end-stage renal disease.

In pediatric patients 6 months to 5 years of age, plasma concentrations following administration of 1.25 mg once daily are similar to those observed in adults receiving 5 mg once daily. In pediatric patients 6-11 years of age, peak plasma concentration and AUC following administration of 5-mg dose are approximately twice that in adults.

Distribution !!navigator!!

Extent

Average apparent volume of distribution is 0.4 L/kg, which represents distribution in total body water.

Expected to distribute into milk.

Plasma Protein Binding

Approximately 91-92% (mainly albumin).

Elimination !!navigator!!

Metabolism

Metabolized to a limited extent (<14% of dose) by aromatic oxidation, N -dealkylation, O -dealkylation, and taurine conjugation.

Elimination Route

Excreted in urine (85.4%) (via glomerular filtration and active tubular secretion) and in feces (12.9%).

<10% of dose removed by standard 4-hour hemodialysis procedure.

Half-life

Approximately 8-9 hours in adults.

Special Populations

In patients with renal impairment, half-life is increased by 1.4-, 2-, or 2.9-fold in those with mild, moderate, or severe impairment, respectively; half-life is increased by fourfold in those with end-stage renal disease. Total body clearance also progressively decreases based on severity of renal impairment. (See Dosage and Administration: Special Populations.)

In pediatric patients 6-11 years of age receiving a single 5-mg dose, total body clearance was 30% greater and elimination half-life 24% shorter than those observed in adults.

In geriatric patients receiving 30 mg once daily for 6 days, total body clearance was 33% lower than that observed in younger adults; however, levocetirizine disposition appears to be dependent on renal function rather than on age.

Description

Levocetirizine is the active R -enantiomer of cetirizine, a second generation antihistamine. The drug exhibits selective antagonism of histamine H1-receptors. In in vitro binding studies, levocetirizine demonstrated a twofold higher affinity for H1-receptors than cetirizine; the clinical relevance of this finding is unknown.

Levocetirizine (at half the dosage of cetirizine) appears to be as potent as cetirizine in inhibiting histamine-induced sneezing, increased nasal airway resistance, and skin wheal and flare; the clinical relevance of histamine wheal skin testing is unknown. Levocetirizine also has been shown to exhibit greater and more consistent inhibition of histamine-induced wheal and flare compared with other antihistamines (e.g., desloratadine, fexofenadine, loratadine).

Levocetirizine is rapidly and extensively absorbed following oral administration; in adults, peak plasma concentrations are attained 0.9 hour following administration of the tablets. Food had no effect on the area under the plasma concentration-time curve (AUC) of levocetirizine following oral administration as tablets; however, time to peak plasma concentration was delayed by about 1.25 hours and peak plasma concentration was decreased by approximately 36% following administration of levocetirizine dihydrochloride tablets with a high fat meal.

The manufacturer states that a 5-mg dose of levocetirizine dihydrochloride administered as the commercially available oral solution containing 2.5 mg/5 mL is bioequivalent to a 5-mg tablet. Following administration of levocetirizine as an oral solution in adults, mean peak plasma concentrations were achieved in approximately 0.5 hours.

Following administration of a single 2.5 or 5-mg dose of levocetirizine dihydrochloride, antihistaminic effects of the drug occur within 1 hour and persist for at least 24 hours. Symptomatic improvement is observed as early as one day after initiation of therapy for allergic rhinitis or chronic idiopathic urticaria.

Levocetirizine is metabolized to a limited extent (less than 14% of the dose) by aromatic oxidation, N -dealkylation, O -dealkylation, and taurine conjugation. The plasma half-life of levocetirizine in adults is approximately 8-9 hours. Approximately 85.4% of the dose is excreted in urine (via glomerular filtration and active tubular secretion), and 12.9% is excreted in feces.

Advice to Patients

Importance of taking only as prescribed; do not exceed prescribed dosage because of increased risk of somnolence.

Risk of somnolence; avoid performing activities requiring complete mental alertness or physical coordination (e.g., operating machinery, driving a motor vehicle).

Avoid concomitant use with alcohol or other CNS depressants.

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.

Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.

Importance of informing patients of other important precautionary information. (See Cautions.)

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Levocetirizine Dihydrochloride

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Solution

2.5 mg/5 mL

Xyzal®

UCB

Tablets, film-coated

5 mg

Xyzal® (scored)

UCB

Copyright

AHFS® Drug Information. © Copyright, 1959-2024, Selected Revisions February 4, 2013. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.

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