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Generic Name: Levocetirizine Dihydrochloride
Class: Second Generation Antihistamines
ATC Class: R06AE09
VA Class: AH109
Chemical Name: [2-[4-[(R)-p-Chloro-α-phenylbenzyl]-1-piperazinyl]ethoxy]acetic acid
Molecular Formula: C21H25ClN2O3
CAS Number: 130018-77-8

Introduction

Second generation antihistamine;34 R-enantiomer of cetirizine.1 2 3 4 5 7 14 15

Uses for Xyzal

Allergic Rhinitis

Symptomatic relief of seasonal (e.g., hay fever) and perennial (nonseasonal) allergic rhinitis.1 5 12 15 32 37 38 39 40

Slideshow: Top Prevention Tips: Springtime Allergies

Chronic Idiopathic Urticaria

Symptomatic treatment of uncomplicated skin manifestations of chronic idiopathic urticaria.1 5 13 14 41

Xyzal Dosage and Administration

Administration

Oral Administration

Administer orally once daily in the evening without regard to meals.1

Tablets are scored and can be broken in half (each half providing a dose of 2.5 mg).1

Dosage

Available as levocetirizine dihydrochloride; dosage expressed in terms of the salt.1

5-mg dose administered as oral solution containing 2.5 mg/5 mL is bioequivalent to 5-mg tablet.1

Pediatric Patients

Allergic Rhinitis
Seasonal
Oral

Children 2–5 years of age: 1.25 mg once daily (as oral solution).1 (See Pediatric Use under Cautions.)

Children 6–11 years of age: 2.5 mg once daily.1

Children ≥12 years of age: 5 mg once daily; alternatively, 2.5 mg once daily may be adequate for some patients.1

Perennial
Oral

Children 6 months to 5 years of age: 1.25 mg once daily (as oral solution).1 (See Pediatric Use under Cautions.)

Children 6–11 years of age: 2.5 mg once daily.1

Children ≥12 years of age: 5 mg once daily; alternatively, 2.5 mg once daily may be adequate for some patients.1

Chronic Idiopathic Urticaria
Oral

Children 6 months to 5 years of age: 1.25 mg once daily (as oral solution).1 (See Pediatric Use under Cautions.)

Children 6–11 years of age: 2.5 mg once daily.1

Children ≥12 years of age: 5 mg once daily; alternatively, 2.5 mg once daily may be adequate for some patients.1

Adults

Allergic Rhinitis
Oral

5 mg once daily; alternatively, 2.5 mg once daily may be adequate for some patients.1

Chronic Idiopathic Urticaria
Oral

5 mg once daily; alternatively, 2.5 mg once daily may be adequate for some patients.1

Prescribing Limits

Pediatric Patients

Allergic Rhinitis
Seasonal
Oral

Children 2–5 years of age: Maximum 1.25 mg daily; higher dosages associated with increased risk of somnolence.1 (See Absorption: Special Populations, under Pharmacokinetics.)

Children 6–11 years of age: Maximum 2.5 mg daily; higher dosages associated with increased risk of somnolence.1

Children ≥12 years of age: Maximum 5 mg daily; higher dosages associated with increased risk of somnolence.1

Perennial
Oral

Children 6 months to 5 years of age: Maximum 1.25 mg daily; higher dosages associated with increased risk of somnolence.1 (See Absorption: Special Populations, under Pharmacokinetics.)

Children 6–11 years of age: Maximum 2.5 mg daily; higher dosages associated with increased risk of somnolence.1

Children ≥12 years of age: Maximum 5 mg daily; higher dosages associated with increased risk of somnolence.1

Chronic Idiopathic Urticaria
Oral

Children 6 months to 5 years of age: Maximum 1.25 mg daily; higher dosages associated with increased risk of somnolence.1 (See Absorption: Special Populations, under Pharmacokinetics.)

Children 6–11 years of age: Maximum 2.5 mg daily; higher dosages associated with increased risk of somnolence.1

Children ≥12 years of age: Maximum 5 mg daily; higher dosages associated with increased risk of somnolence.1

Adults

Allergic Rhinitis
Oral

Maximum 5 mg daily;1 higher dosages associated with increased risk of somnolence.1 15

Chronic Idiopathic Urticaria
Oral

Maximum 5 mg daily;1 higher dosages associated with increased risk of somnolence.1 15

Special Populations

Hepatic Impairment

No dosage adjustment required.1

Renal Impairment

Children 6 months to 11 years of age: Use contraindicated.1 (See Contraindications under Cautions.)

Adults and children ≥12 years of age: Adjust dosage based on 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 with Renal Impairment133

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

Geriatric Patients

Select dosage with caution (usually starting at low end of dosage range) because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.1 (See Geriatric Use under Cautions.)

Cautions for Xyzal

Contraindications

  • Known hypersensitivity (e.g., urticaria, anaphylaxis) to levocetirizine or any ingredient in the formulation, or to cetirizine.1

  • Adults and children ≥12 years of age with end-stage renal disease (Clcr <10 mL/minute) or undergoing hemodialysis.1

  • Pediatric patients 6 months to 11 years of age with renal impairment.1

Warnings/Precautions

CNS Effects

Somnolence, fatigue, and asthenia reported.1 7 12 13 15 Avoid performing hazardous activities requiring complete mental alertness or physical coordination (e.g., operating machinery, driving a motor vehicle).1 (See Advice to Patients.)

Specific Populations

Pregnancy

Category B.1

Lactation

Expected to distribute into milk (since cetirizine is distributed into milk).1 Use not recommended.1

Pediatric Use

Safety not established in children <6 months of age.1 36

Efficacy of 1.25-mg once daily dosage (in pediatric patients 6 months to 5 years of age years of age) and 2.5-mg daily dosage (in pediatric patients 6–11 years of age) for management of allergic rhinitis is based on extrapolation of demonstrated efficacy of 5-mg daily dosage in pediatric patients ≥12 years of age and on pharmacokinetic comparisons in adults and children.1

Efficacy of 1.25-mg once daily dosage (in pediatric patients 6 months to 5 years of age years of age), 2.5-mg daily dosage (in pediatric patients 6–11 years of age), and 5-mg daily dosage (in pediatric patients ≥12 years of age) for management of chronic idiopathic urticaria is based on extrapolation of demonstrated efficacy in adults and/or on pharmacokinetic comparisons in adults and children.1

Risk of overdosage and toxicity (including death) in children <2 years of age receiving 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

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults.1 Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.1 (See Geriatric Patients under Dosage and Administration.) Periodic monitoring of renal function may be useful.1

Hepatic Impairment

Pharmacokinetics not evaluated, but clearance unlikely to be decreased.1 (See Elimination under Pharmacokinetics.) Dosage adjustment not necessary.1

Renal Impairment

Decreased clearance, resulting in increased risk of adverse effects.1 Dosage adjustment necessary based on degree of renal impairment.1 (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

Children 6–11 months of age (with 1.25-mg once daily dosage): Diarrhea,1 constipation.1

Children 1–5 years of age (with 1.25-mg twice daily dosage): Pyrexia,1 diarrhea,1 vomiting,1 otitis media.1

Children 6–12 years of age (with 5-mg daily dosage): Pyrexia,1 cough,1 somnolence,1 epistaxis.1 6

Adults and children ≥12 years of age (with 2.5- or 5-mg daily dosage): Somnolence,1 5 15 32 nasopharyngitis,1 fatigue,1 5 15 32 dry mouth,1 5 15 pharyngitis.1 32

Interactions for Xyzal

No formal drug interaction studies with levocetirizine to date; studies have been performed with racemic cetirizine.1 (See Specific Drugs under Interactions.)

Does not inhibit CYP isoenzymes 1A2, 2C9, 2C19, 2A1, 2D6, 2E1, or 3A4.1 5 Does not induce UGT1A or CYP isoenzymes 1A2, 2C9, or 3A4.1 Unlikely to produce or be subject to pharmacokinetic interactions associated with metabolic enzyme systems.1

Specific Drugs

Drug

Interaction

Comments

Azithromycin

No clinically important changes in ECG parameters observed following concomitant use with cetirizine, and no clinically important interactions reported following such concomitant use1 16 17 20 21

Cimetidine

No pharmacokinetic interactions observed with cetirizine1

CNS depressants (e.g., alcohol)

Possible additive CNS effects1

Avoid concomitant use1

Erythromycin

No clinically important changes in ECG parameters observed following concomitant use with cetirizine, and no clinically important interactions reported following such concomitant use1 16 17 20 21

Ketoconazole

Prolongation of QTc interval (with an increase of 17.4 msec) observed following concomitant administration with cetirizine; no other clinically important interactions reported following such concomitant use1 16 21 22

Not considered clinically important16 21 22

Pseudoephedrine

No pharmacokinetic interactions observed with cetirizine1 16 17

Ritonavir

Increased plasma AUC (42%), increased half-life (53%), and decreased clearance (29%) of cetirizine; disposition of ritonavir not altered following concomitant administration with cetirizine1

Theophylline

Decreased clearance (16%) of cetirizine; disposition of theophylline not altered following concomitant administration with cetirizine1 16 17

Xyzal Pharmacokinetics

Absorption

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).1 5 18

Onset

Antihistaminic effects occur within 1 hour.1 2 7 19 Symptomatic improvement observed as early as 1 day after initiation of therapy for allergic rhinitis1 7 8 15 or chronic idiopathic urticaria.13 14 33

Duration

Antihistaminic effects persist for at least 24 hours.1 2 6 7 8 15 19

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.1

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.1

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.1 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.1

Distribution

Extent

Average apparent volume of distribution is 0.4 L/kg, which represents distribution in total body water.1

Expected to distribute into milk.1

Plasma Protein Binding

Approximately 91–92%1 (mainly albumin).5 33

Elimination

Metabolism

Metabolized to a limited extent (<14% of dose) by aromatic oxidation, N-dealkylation, O-dealkylation, and taurine conjugation.1

Elimination Route

Excreted in urine (85.4%) (via glomerular filtration and active tubular secretion) and in feces (12.9%).1 18

<10% of dose removed by standard 4-hour hemodialysis procedure.1

Half-life

Approximately 8–9 hours in adults.1

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.1 Total body clearance also progressively decreases based on severity of renal impairment.1 (See Renal Impairment under Dosage and Administration.)

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.1

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.1

Stability

Storage

Oral

Tablets and Oral Solution

20–25ºC (may be exposed to 15–30ºC).1 33

Actions

  • Exhibits selective antagonism of peripheral histamine H1-receptors.1

  • At half the dosage of cetirizine, appears to be as potent as cetirizine in inhibiting histamine-induced sneezing,4 increased nasal airway resistance,3 4 5 and skin wheal and flare.2 3 5

  • 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).5 7 19 Clinical relevance of histamine wheal skin testing is unknown.1

Advice to Patients

  • Importance of taking only as prescribed; do not exceed prescribed dosage because of increased risk of somnolence.1

  • Risk of somnolence;1 7 12 15 avoid performing activities requiring complete mental alertness or physical coordination (e.g., operating machinery, driving a motor vehicle).1

  • Avoid concomitant use with alcohol or other CNS depressants.1

  • 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.1

  • Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

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

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

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Levocetirizine Dihydrochloride 2.5MG/5ML Solution (WINTHROP US): 148/$89.99 or 444/$249.96

Levocetirizine Dihydrochloride 5MG Tablets (WINTHROP US): 30/$89.99 or 90/$249.97

Xyzal 2.5MG/5ML Solution (SANOFI-AVENTIS U.S.): 148/$101.99 or 444/$299.96

Xyzal 5MG Tablets (SANOFI-AVENTIS U.S.): 90/$298.78 or 270/$855.82

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions February 4, 2013. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. UCB Inc. Xyzal (levocetirizine dihydrochloride) tablets and oral solution prescribing information. 2010 Dec. From website.

2. Devalia JL, De Vos C, Hanotte F et al. A randomized, double-blind, crossover comparison among cetirizine, levocetirizine, and ucb 28557 on histamine-induced cutaneous responses in healthy adult volunteers. Allergy. 2001; 56:50-57. [PubMed 11167352]

3. Tillement JP, Testa B, Brée F. Compared pharmacological characteristics in humans of racemic cetirizine and levocetirizine, two histamine H1-receptor antagonists. Biochem Pharmacol. 2003; 66:1123-6. [PubMed 14505791]

4. Wang DY, Hanotte F, De Vos C et al. Effect of cetirizine, levocetirizine, and dextrocetirizine on histamine-induced nasal response in healthy adult volunteers. Allergy. 2001; 56:339-43. [PubMed 11284803]

5. Ciprandi G, Cirillo I, Vizzaccaro A, Tosca MA. Levocetirizine improves nasal obstruction and modulates cytokine pattern in patients with seasonal allergic rhinitis: a pilot study. Clin Exp Allergy. 2004; 34(6): 958-964. [PubMed 15196286]

6. de Blic J, Wahn U, Billard E et al. Levocetirizine in children: evidenced efficacy and safety in a 6-week randomized seasonal allergic rhinitis trial. Pediatr Allergy Immunol. 2005; 16:267-75. [PubMed 15853959]

7. Day JH, Briscoe MP, Rafeiro E et al. Comparative clinical efficacy, onset and duration of action of levocetirizine and desloratadine for symptoms of seasonal allergic rhinitis in subjects evaluated in the Environmental Exposure Unit (EEU). Int J Clin Pract. 2004; 58:109-18. [PubMed 15055856]

8. Horak F, Zieglmayer PU, Zieglmayer R et al. Levocetirizine has a longer duration of action on improving total nasal symptoms score than fexofenadine after single administration. Br J Clin Pharmacol. 2005; 60:24-31. [PubMed 15963090]

9. Ciebiada M, Gorska-Ciebiada M, DuBuske LM et al. Montelukast with desloratadine or levocetirizine for the treatment of persistent allergic rhinitis. Ann Allergy Asthma Immunol. 2006; 97:664-71. [PubMed 17165277]

10. Pasquali M, Baiardini I, Rogkakou A et al. Levocetirizine in persistent allergic rhinitis and asthma: effects on symptoms, quality of life and inflammatory parameters. Clin Exp Allergy. 2006; 36:1161-7. [PubMed 16961716]

11. Potter PC for the Paediatric Levocetirizine Study Group. Efficacy and safety of levocetirizine on symptoms and health-related quality of life of children with perennial allergic rhinitis: a double-blind, placebo-controlled randomized clinical trial. Ann Allergy Asthma Immunol. 2005; 95:175-80. [PubMed 16136768]

12. Potter PC for the Study Group. Levocetirizine is effective for symptom relief including nasal congestion in adolescent and adult (PAR) sensitized to house dust mites. Allergy. 2003; 58:893-9. [PubMed 12911418]

13. Kapp A, Pichler WJ. Levocetirizine is an effective treatment in patients suffering from chronic idiopathic urticaria: a randomized, double-blind, placebo-controlled, parallel, multicenter study. Int J Dermatol. 2006; 45:469-74. [PubMed 16650180]

14. Nettis E, Colanardi MC, Barra L et al. Levocetirizine in the treatment of chronic idiopathic urticaria: a randomized, double-blind, placebo-controlled study. Br J Dermatol. 2006; 154:533-8. [PubMed 16445787]

15. Leynadier F, Mees K, Arendt C et al. Efficacy and safety of levocetirizine in seasonal allergic rhinitis. Acta Otorhinolaryngol Belg. 2001; 55:305-12. [PubMed 11859651]

16. Pfizer Labs. Zyrtec (cetirizine hydrochloride) tablets and syrup prescribing information. New York, NY; 2004 Jul.

17. Pfizer Laboratories. Zyrtec (cetirizine hydrochloride) tablets product monograph. New York, NY: Undated.

18. Benedetti MS, Plisnier M, Kaise J et al. Absorption, distribution, metabolism and excretion of [14C] levocetirizine, the R enantiomer of cetirizine, in healthy volunteers. Eur J Clin Pharmacol. 2001; 57:571-82. [PubMed 11758635]

19. Grant JA, Riethuisen JM, Moulaert B et al. A double-blind, randomized, single-dose, crossover comparison of levocetirizine with ebastine, fexofenadine, loratadine, mizolastine, and placebo: suppression of histamine-induced wheal-and-flare response during 24 hours in healthy male subjects. Ann Allergy Asthma Immunol. 2002; 88:190-7. [PubMed 11868924]

20. Simons FER. H1-Receptor antagonists: comparative tolerability and safety. Drug Saf. 1994; 10:350-80. [IDIS 359177] [PubMed 7913608]

21. Reviewers’ comments (for cetirizine).

22. Pfizer Inc. Manufacturer’s comments (for cetirizine).

23. Borge PA. Problems in allergic rhinitis. Arzneimittelforschung. 1982; 32:1199-201. [PubMed 6891258]

24. Anon. Treatment of seasonal and perennial rhinitis. BMJ. 1981; 283:808-10. [PubMed 6117350]

25. Food and Drug Administration. Over-the-counter drugs: establishment of a monograph for OTC cold, cough, allergy, bronchodilator and antiasthmatic products. [21 CFR 341] Fed Regist. 1976; 41:38312-424.

26. Douglas WW. Histamine and 5-hydroxytryptamine (serotonin) and their antagonists. In: Gilman AG, Goodman LS, Rall TW et al, eds. Goodman and Gilman’s the pharmacologic basis of therapeutics. 7th ed. New York: Macmillan Publishing Company; 1985:605-38.

27. Cirillo VJ, Tempero KF. The pharmacology and therapeutic use of H1 and H2 antihistamines. In: Miller RR, Greenblatt DJ, eds. Drug therapy reviews. Vol 2. New York: Elsevier/North Holland Inc; 1979:24-47.

28. AMA Division of Drugs. AMA drug evaluations. 5th ed. Chicago: American Medical Association; 1983:1465-79.

29. Church JA. Allergic rhinitis: diagnosis and management. Clin Pediatr (Philadelphia). 1980; 19:655-9.

30. Food and Drug Administration. Cold, cough, allergy, bronchodilator, and antiasthmatic drug products for over-the-counter human use; tentative final monograph for OTC antihistamine drug products. [21 FR Part 341] Fed Regist. 1985; 50:2200-18.

31. Holgate S. Comparative trial of two non-sedative H1 antihistamines, terfenadine and astemizole, for hay fever. Thorax. 1985; 40:399.

32. Bachert C, Bousquet J, Canonica W et al for the XPERT Study Group. Levocetirizine improves quality of life and reduces costs in long-term management of persistent allergic rhinitis. J Allergy Clin Immunol. 2004; 114:838-44. [PubMed 15480324]

33. UCB, Inc., Smyrna, GA: Personal communication.

34. Anon. Drugs for allergic disorders. Treat Guidel Med Lett. 2007; 5:71-80.

36. Hampel F, Ratner P, Haeusler JM. Safety and tolerability of levocetirizine dihydrochloride in infants and children with allergic rhinitis or chronic urticaria. Allergy Asthma Proc. 2010 Jul-Aug; 31:290-5.

37. Segall N, Gawchik S, Georges G et al. Efficacy and safety of levocetirizine in improving symptoms and health-related quality of life in US adults with seasonal allergic rhinitis: a randomized, placebo-controlled study. Ann Allergy Asthma Immunol. 2010; 104:259-67. [PubMed 20377116]

38. Day JH, Briscoe MP, Ratz JD. Efficacy of levocetirizine compared with montelukast in subjects with ragweed-induced seasonal allergic rhinitis in the Environmental Exposure Unit. Allergy Asthma Proc. 2008 May-Jun; 29:304-12.

39. Patel P, Patel D. Efficacy comparison of levocetirizine vs montelukast in ragweed sensitized patients. Ann Allergy Asthma Immunol. 2008; 101:287-94. [PubMed 18814452]

40. Walter Canonica G, Bousquet J, Van Hammée G et al. Levocetirizine improves health-related quality of life and health status in persistent allergic rhinitis. Respir Med. 2006; 100:1706-15. [PubMed 16723217]

41. Potter PC, Kapp A, Maurer M et al. Comparison of the efficacy of levocetirizine 5 mg and desloratadine 5 mg in chronic idiopathic urticaria patients. Allergy. 2009; 64:596-604. [PubMed 19053988]

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