Xyzal - Drug Monograph

Introduction

Xyzal (levocetirizine dihydrochloride) is a second-generation, peripherally selective H1-receptor antagonist used primarily for the symptomatic relief of allergic rhinitis and chronic spontaneous urticaria. As the pharmacologically active R-enantiomer of cetirizine, it offers comparable efficacy at half the racemic dose with a favorable sedation profile. It is widely prescribed in both adult and pediatric populations and is available by prescription and, in some jurisdictions, over the counter.

Drug Class and Overview

• Class: Second-generation (non-sedating) antihistamine; selective peripheral H1-receptor antagonist.
• Related agents: Cetirizine (racemate), loratadine, desloratadine, fexofenadine, ebastine, bilastine.
• Distinguishing features:
• Single R-enantiomer of cetirizine; approximately twice the H1-binding affinity of the racemate.
• Minimal penetration across the blood–brain barrier at therapeutic doses, reducing central nervous system (CNS) effects relative to first-generation agents.
• Negligible hepatic metabolism via cytochrome P450 enzymes, lowering the potential for CYP-mediated drug interactions.
• Available as oral tablets (5 mg) and oral solution (0.5 mg/mL); also marketed in some regions as orally disintegrating tablets.

Mechanism of Action

Levocetirizine competitively and reversibly binds to peripheral H1 histamine receptors, preventing endogenous histamine from eliciting the classic allergic response (vasodilation, increased vascular permeability, pruritus, bronchoconstriction, and smooth-muscle contraction). It does not appreciably block H2, muscarinic, serotonergic, or α-adrenergic receptors at therapeutic concentrations. Anti-inflammatory properties—including suppression of eosinophil migration, decreased ICAM-1 expression on epithelial cells, and inhibition of leukotriene and cytokine release—have been described in vitro and in small clinical studies, although these are considered secondary to H1 antagonism.

Indications

• Allergic rhinitis (seasonal and perennial): Relief of nasal symptoms (rhinorrhea, sneezing, nasal pruritus, congestion) and ocular symptoms (itching, tearing, redness).
• Chronic spontaneous (idiopathic) urticaria: Reduction of wheal size, number, and pruritus.
• Off-label / adjunctive uses (evidence variable): Atopic dermatitis-associated pruritus, mild allergic asthma adjunct, and mosquito-bite hypersensitivity. Use in these settings is not FDA-approved.

Dosage and Administration

• Adults and adolescents ≥12 years: 5 mg orally once daily (in the evening is often recommended due to potential mild sedation).
• Pediatric patients 6–11 years: 2.5 mg (½ tablet or 5 mL of the 0.5 mg/mL solution) once daily.
• Pediatric patients 2–5 years: 1.25 mg (2.5 mL of the 0.5 mg/mL solution) once daily.
• Pediatric patients 6 months–5 years (per FDA labeling for chronic urticaria): 1.25 mg once daily; dosing for allergic rhinitis in this age group is not established in the U.S. label.
• Renal impairment (adults):
• CrCl 50–80 mL/min: 5 mg daily.
• CrCl 30–50 mL/min: 5 mg every other day.
• CrCl 10–30 mL/min: 5 mg twice weekly (every 3–4 days).
• CrCl <10 mL/min or on hemodialysis: contraindicated.
• Hepatic impairment: No dosage adjustment generally required because hepatic metabolism is minimal; however, caution is advised in combined hepatorenal dysfunction.
• Geriatric patients: Dose selection should be cautious, reflecting greater frequency of reduced renal function.
• Pregnancy: Category B (U.S. FDA legacy classification). Use only if clearly needed; data are limited.
• Lactation: Cetirizine/levocetirizine are excreted in breast milk; use with caution.

Pharmacokinetics

• Absorption: Rapidly and extensively absorbed after oral administration; peak plasma concentration (Tmax) reached in approximately 0.9–1 hour. Food does not significantly alter the extent of absorption but may delay Tmax.
• Distribution: Approximately 90% protein-bound. Volume of distribution is modest; limited CNS penetration at therapeutic doses.
• Metabolism: Less than 14% of an oral dose undergoes hepatic metabolism (via aromatic oxidation, N- and O-dealkylation, taurine conjugation). CYP3A4, CYP2D6, and CYP2C9 play minor roles; no clinically significant CYP inhibition or induction.
• Elimination: Primarily renal—about 85% excreted unchanged in urine via glomerular filtration and active tubular secretion. The remainder appears in feces.
• Half-life: Approximately 8 hours in adults with normal renal function; prolonged in renal impairment (up to ~24 hours in severe impairment).
• Onset of action: Symptom relief typically within 1 hour; full effect within a few hours of steady-state dosing.

Contraindications

• Known hypersensitivity to levocetirizine, cetirizine, hydroxyzine, or any component of the formulation.
• End-stage renal disease (CrCl <10 mL/min) or patients on hemodialysis.
• Pediatric patients with known risk factors for urinary retention (e.g., spinal cord lesions, prostatic hypertrophy) should generally avoid use.

Warnings and Precautions

• Somnolence / CNS depression: Although classified as non-sedating, dose-related drowsiness can occur. Caution when driving, operating machinery, or combining with other CNS depressants (alcohol, benzodiazepines, opioids, sleep aids).
• Urinary retention: Anticholinergic-like effects on the bladder, though minimal, may precipitate retention in predisposed patients (e.g., prostatic hypertrophy, neurogenic bladder).
• Renal impairment: Dose reduction required; accumulation can occur and increase adverse effects.
• Hepatic impairment: Use cautiously when hepatic disease coexists with renal dysfunction.
• Discontinuation of antihistamines prior to allergy skin testing: Although levocetirizine has a relatively short half-life, standard practice is to discontinue antihistamines for a defined period (often 3–7 days) before skin-prick or intradermal testing to avoid false-negative results.
• Pediatric considerations: Somnolence may be more apparent in young children; monitor for paradoxical excitation.

Drug Interactions

• CNS depressants (alcohol, benzodiazepines, barbiturates, opioids, sedative antihistamines, sleep aids): Additive sedation; counsel patients and consider dose adjustments.
• Anticholinergic agents (e.g., tricyclic antidepressants, oxybutynin, benztropine): Potential additive anticholinergic effects, including dry mouth, constipation, and urinary retention.
• Theophylline: A small decrease in the clearance of theophylline has been reported with cetirizine; clinical significance with levocetirizine is uncertain.
• Ritonavir / P-glycoprotein inhibitors: Levocetirizine is a substrate of renal organic anion transporters; theoretically, drugs that inhibit tubular secretion (e.g., probenecid) could increase plasma concentrations, though clinical impact is generally minor.
• CYP-mediated interactions: Negligible; levocetirizine does not significantly inhibit or induce CYP1A2, 2C9, 2C19, 2D6, 2E1, or 3A4.

Adverse Effects

• Common (≥1%): Somnolence, fatigue, dry mouth, headache, dizziness, pharyngitis, nasopharyngitis, abdominal pain.
• Less common: Nausea, dyspepsia, increased appetite, weight gain, epistaxis, cough, palpitations.
• Rare / serious: Hypersensitivity reactions (urticaria, angioedema, anaphylaxis), seizures (predominantly in overdose or predisposed patients), hepatitis, cholestasis, visual disturbances, urinary retention, aggression/behavioral changes (reported in children), thrombocytopenia.
• Overdose: Drowsiness, agitation, restlessness, tachycardia; treatment is supportive; hemodialysis is not effective due to high protein binding.

Monitoring Parameters

• Clinical response: Symptom diary for nasal/ocular symptoms or urticaria activity (e.g., Urticaria Activity Score).
• Renal function: Serum creatinine or estimated CrCl at baseline in older adults and any patient with suspected renal disease; adjust dose accordingly.
• Adverse effects: Inquiry about sedation, dry mouth, urinary symptoms, and paradoxical CNS effects at follow-up.
• Pregnancy/lactation status: Reassess risk-benefit if pregnancy is discovered during therapy.

Patient Education

• Take once daily, preferably in the evening; consistent timing improves symptom control.
• May be taken with or without food; avoid alcohol and other sedating medications unless approved by your clinician.
• Do not drive or operate machinery until you know how the medication affects you.
• If you have kidney disease, inform your clinician—dose adjustment may be needed.
• For allergy skin testing, stop the medication at least several days before the test (per your allergist's instructions).
• Report any difficulty urinating, severe drowsiness, swelling of the face/tongue, or unusual behavioral changes.
• Store at room temperature, away from moisture and heat; keep out of reach of children.

Clinical Pearls

1. Levocetirizine is the active R-enantiomer of cetirizine—twice the H1 affinity, allowing a 5 mg dose to deliver efficacy comparable to 10 mg of cetirizine.
2. Despite being labeled "non-sedating," somnolence is the most common dose-limiting side effect; counsel patients and consider evening dosing.
3. Renal dosing is essential: the drug is excreted largely unchanged, and accumulation in renal impairment can amplify CNS and anticholinergic effects.
4. Minimal CYP metabolism makes levocetirizine one of the safer antihistamines for patients on multiple chronic medications, including the elderly.
5. Discontinue before allergy skin testing to avoid false-negative results; the washout period is generally shorter than for long-acting first-generation agents but should still be observed.
6. In chronic urticaria unresponsive to standard doses, up-dosing (up to 20 mg daily in adults) has been studied and is recommended in some international guidelines before adding alternative agents.

References

1. U.S. Food and Drug Administration. Xyzal (levocetirizine dihydrochloride) Prescribing Information. Sanofi-Aventis U.S. LLC.
2. Day JH, et al. Comparative efficacy of cetirizine and levocetirizine in allergic rhinitis and urticaria. Allergy clinical reviews (standard review literature).
3. Bousquet J, et al. Allergic Rhinitis and its Impact on Asthma (ARIA) Guidelines. Allergy.
4. Bernstein JA, et al. Joint Task Force Practice Parameter: The diagnosis and management of acute and chronic urticaria. Annals of Allergy, Asthma & Immunology.
5. Krouse JH, et al. Clinical practice guideline: Allergic rhinitis. Otolaryngology–Head and Neck Surgery (AAO-HNS).
6. Brunton LL, Knollmann BC (eds). Goodman & Gilman's The Pharmacological Basis of Therapeutics. McGraw-Hill (histamine and antihistamine chapter).
7. Katzung BG, Vanderah TW (eds). Basic and Clinical Pharmacology. McGraw-Hill (antihistamines section).
8. Lexicomp Online. Levocetirizine: Drug Information. Wolters Kluwer.
9. American Academy of Allergy, Asthma & Immunology (AAAAI). Allergic Rhinitis Treatment Guidelines.
10. Simons FER. Advances in H1-antihistamines. New England Journal of Medicine (review article on second-generation antihistamines).