Xyzal

Xyzal

levocetirizine

Manufacturer:

GlaxoSmithKline

Distributor:

Zuellig
Full Prescribing Info
Contents
Levocetirizine diHCl.
Description
Levocetirizine dihydrochloride (Xyzal) 5 mg Tablet: Each white to off-white, oval, film-coated tablet with a Y logo on one side, contains 5 mg of levocetirizine as dihydrochloride. Levocetirizine dihydrochloride (Xyzal) 5 mg/mL Solution (Oral Drops): Each mL of clear and colourless liquid solution contains 5 mg of levocetirizine as dihydrochloride. Levocetirizine dihydrochloride (Xyzal) 500 mcg/mL Oral Solution: Each mL of clear and colourless liquid solution contains 500mcg of levocetirizine as dihydrochloride.
Excipients/Inactive Ingredients: Levocetirizine dihydrochloride, 5 mg, film-coated tablet: Microcrystalline cellulose, Lactose monohydrate, Colloidal anhydrous silica, Magnesium stearate, Hypromellose, Titanium dioxide, Macrogol 400.
Levocetirizine dihydrochloride, 5 mg/ml, oral drops, solution: Sodium acetate, Acetic acid, Propylene glycol, Glycerol 85% , Methyl parahydroxybenzoate, Propyl parahydroxybenzoate, Saccharin sodium, Purified water.
Levocetirizine dihydrochloride, 500 mcg/mL, oral solution: Sodium acetate, Acetic acid, Methyl parahydroxybenzoate (E218), Propyl parahydroxybenzoate (E216), Glycerol 85%, Maltitol, Saccharin sodium, Tutti frutti flavour, Purified water.
Action
Pharmacotherapeutic Group: Antihistamine for systemic use, piperazine derivative.
Pharmacology: Pharmacodynamics: Mechanism of Action/Pharmacodynamic Effects: Levocetirizine, the (R) enantiomer of cetirizine, is a potent and selective antagonist of peripheral H1-receptors. Binding studies revealed that levocetirizine has high affinity for human H1-receptors (Ki=3.2 nmol/L). Levocetirizine has an affinity 2-fold higher than that of cetirizine (Ki=6.3 nmol/L). Levocetirizine dissociates from H1-receptors with a t½ of 115±38 min.
After single administration, levocetirizine shows a receptor occupancy of 90% at 4 hrs and 57% at 24 hrs. Pharmacodynamic studies in healthy volunteers demonstrate that, at half the dose, levocetirizine has comparable activity to cetirizine, both in the skin and in the nose.
The pharmacodynamic activity of levocetirizine has been studied in randomized, controlled trials: In a study comparing the effects of levocetirizine 5 mg, desloratadine 5 mg and placebo on histamine-induced wheal and flare, levocetirizine treatment resulted in significantly decreased wheal and flare formation which was highest in the first 12 hrs and lasted for 24 hrs (p<0.001), compared with placebo and desloratadine.
The onset of action of levocetirizine 5 mg in controlling pollen-induced symptoms has been observed at 1-hr post-drug intake in placebo-controlled trials in the model of the allergen challenge chamber.
In vitro studies (Boyden chambers and cell layers techniques) show that levocetirizine inhibits eotaxin-induced eosinophil transendothelial migration through both dermal and lung cells. A pharmacodynamic experimental study in vivo (skin chamber technique) showed 3 main inhibitory effects of levocetirizine 5 mg in the first 6 hrs of pollen-induced reaction, compared with placebo in 14 adult patients: Inhibition of vascular cell adhesion molecule 1 (VCAM-1) release, modulation of vascular permeability and a decrease in eosinophil recruitment.
Clinical Studies: The efficacy and safety of levocetirizine has been demonstrated in several double-blind, placebo-controlled, clinical trials performed in adult patients suffering from seasonal, perennial or persistent allergic rhinitis. Levocetirizine has been shown to significantly improve symptoms of allergic rhinitis including nasal obstruction in some studies.
A 6-month clinical study in 551 patients (including 278 levocetirizine-treated patients) suffering from persistent allergic rhinitis (symptoms present 4 days a week for at least 4 consecutive weeks) and sensitized to house dust mites and grass pollen demonstrated that levocetirizine 5 mg was clinically and statistically significantly more potent than placebo on the relief from the total symptom score of allergic rhinitis throughout the whole duration of the study, without any tachyphylaxis. During the whole duration of the study, levocetirizine significantly improved the quality of life of the patients.
The pediatric safety and efficacy of levocetirizine tablets has been studied in 2 placebo-controlled clinical trials, including patients 6-12 years and suffering from seasonal and perennial allergic rhinitis, respectively. In both trials, levocetirizine significantly improved symptoms and increased health-related quality of life.
In a placebo-controlled clinical trial including 166 patients suffering from chronic idiopathic urticaria, 85 patients were treated with placebo and 81 patients with levocetirizine 5 mg once daily >6 weeks. Treatment with levocetirizine resulted in significant decrease in pruritus severity over the 1st week and over the total treatment period as compared to placebo. Levocetirizine also resulted in a larger improvement of health-related quality of life as assessed by the Dermatology Life Quality Index as compared to placebo. Chronic idiopathic urticaria was studied as a model for urticarial conditions. Since histamine release is a causal factor in urticarial diseases, levocetirizine is expected to be effective in providing symptomatic relief for other urticarial conditions in addition to chronic idiopathic urticaria.
Pharmacokinetic/Pharmacodynamic Relationship: The action on histamine-induced skin reactions is out of phase with the plasma concentrations. Electrocardiograms (ECGs) did not show relevant effects of levocetirizine on QT interval.
Pediatric Data for Oral Drops and Oral Solution: In children <6 years, clinical safety has been established from several short- or long-term therapeutic studies: One (1) clinical trial in which 29 children 2-6 years with allergic rhinitis were treated with levocetirizine 1.25 mg twice daily for 4 weeks.
One (1) clinical trial in which 114 children 1-5 years with allergic rhinitis or chronic idiopathic urticaria were treated with levocetirizine 1.25 mg twice daily for 2 weeks.
One (1) clinical trial in which 45 children 6-11 months with allergic rhinitis or chronic idiopathic urticaria were treated with levocetirizine 1.25 mg once daily for 2 weeks.
One (1) long-term (18 months) clinical trial in 255 levocetirizine-treated atopic subjects aged 12-24 months at inclusion.
The safety profile was similar to that seen in the short-term studies conducted in children 1-5 years.
Pharmacokinetics: The pharmacokinetics of levocetirizine are linear with dose- and time-dependent with intersubject variability. The pharmacokinetic profile is the same when given as the single enantiomer or when given as cetirizine. No chiral inversion occurs during the process of absorption and elimination.
Absorption: Levocetirizine is rapidly and extensively absorbed following oral administration. In adults, peak plasma concentrations (Cmax) are achieved 0.9 hr after dosing. Steady state is 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. The extent of absorption is dose-independent and is not altered by food, but the peak concentration is reduced and delayed.
Distribution: No tissue distribution data are available in humans, neither concerning the passage of levocetirizine through the blood-brain barrier. In rats and dogs, the highest tissue levels are found in liver and kidneys, the lowest in the central nervous system (CNS) compartment. In humans, levocetirizine is 90% bound to plasma proteins. The distribution of levocetirizine is restrictive, as the volume of distribution is 0.4 L/kg.
Metabolism: The extent of metabolism of levocetirizine in humans is <14% of the dose and therefore, differences resulting from genetic polymorphism or concomitant intake of 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 involved multiple and/or unidentified CYP isoforms. Levocetirizine had no effect on the activities of CYP isoenzymes 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4 at concentrations well above peak concentrations achieved following a 5-mg oral dose.
Due to its low metabolism and absence of metabolic inhibition potential, the interaction of levocetirizine with other substances or vice versa, is unlikely.
Elimination: The plasma t½ in adults is 7.9±1.9 hrs. The mean apparent total body clearance in adults is 0.63 mL/min/kg. The major route of excretion of levocetirizine and 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.
Children: Data from a pediatric pharmacokinetic study with oral administration of a single dose of levocetirizine 5 mg in 14 children 6-11 years with body weight ranging between 20 and 40 kg show that Cmax and area under the concentration-time curve (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 hrs, weight-normalized, total body clearance was 30% greater and the elimination t½ 24% shorter in this pediatric population than in adults. Dedicated pharmacokinetic studies have not been conducted in pediatric patients <6 years. A retrospective population pharmacokinetic analysis was conducted in 324 subjects (181 children 1-5 years, 18 children 6-11 years, and 124 adults 18-55 years) who received single or multiple doses of levocetirizine ranging from 1.25-30 mg. Data generated from this analysis indicated that administration of 1.25 mg once daily to children 6 months to 5 years is expected to result in plasma concentrations similar to those of adults receiving 5 mg once daily.
Elderly: Limited pharmacokinetic data are available in elderly subjects. Following once daily repeat oral administration of levocetirizine 30 mg for 6 days in 9 elderly subjects (65-74 years), 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 levocetirizine dose should be adjusted in accordance with renal function in elderly patients.
Renal Impairment: The apparent body clearance of levocetirizine is correlated to the creatinine clearance. It is therefore recommended to adjust the dosing intervals of levocetirizine based on creatinine clearance (CrCl) in patients with moderate and severe renal impairment. In anuric end-stage renal disease subjects, the total body clearance is decreased by approximately 80% when compared to normal subjects. The amount of levocetirizine removed during a standard 4-hr hemodialysis procedure was <10%.
Hepatic Impairment: The pharmacokinetics of levocetirizine in hepatically impaired subjects have not been tested. Patients with chronic liver diseases (hepatocellular, cholestatic and biliary cirrhosis) given 10 mg or 20 mg of the racemic compound cetirizine as a single dose had a 50% increase in t½ along with a 40% decrease in clearance compared to healthy subjects.
Other Patient Characteristics: Gender: Pharmacokinetic results for 77 patients (40 men, 37 women) were evaluated for potential effect of gender. The t½ was slightly shorter in women (7.08±1.72 hrs) than in men (8.62±1.84 hrs); 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.
Race: The effect of race on levocetirizine has not been studied. As levocetirizine is primarily renally excreted, and there are no important racial differences in CrCl, 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.
Toxicology: Nonclinical Information: Nonclinical data revealed no special hazard for humans based on conventional studies of safety pharmacology, repeated-dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction.
Indications/Uses
Symptomatic treatment of allergic rhinitis (including persistent allergic rhinitis) and urticaria.
Dosage/Direction for Use
Route of Administration: For oral use.
Adults and Adolescents ≥12 years:
5 mg once daily (1 film-coated tablet or 10 mL of solution or 20 drops).
Children 6-12 years: 5 mg once daily (1 film-coated tablet or 10 mL of solution or 20 drops). No adjusted dosage is possible with the film-coated tablet. It is recommended to use a pediatric formulation of levocetirizine (see Precautions).
Children 2-6 years: 2.5 mg to be administered in 2 intakes of 1.25 mg (2.5 mL of solution or 5 drops twice daily).
Elderly with Renal Impairment: Adjustment of the dose is recommended in elderly patients with moderate to severe renal impairment (see Renal Impairment as follows).
Renal Impairment: The dosing intervals must be individualized according to renal function. Refer to the table as follows and adjust the dose as indicated. To use the dosing table, an estimate of the patient's CrCl in mL/min is needed. (See table.) The CrCl (mL/min) may be estimated from serum creatinine (mg/dL) determination using the following formula:

Click on icon to see table/diagram/image


Click on icon to see table/diagram/image

In pediatric patients suffering from renal impairment, the dose will have to be adjusted on an individual basis, taking into account the renal clearance of the patient and his body weight. There are no specific data for children with renal impairment.
Hepatic Impairment: No dose adjustment is needed in patients with solely hepatic impairment. In patients with hepatic and renal impairment, adjustment of the dose is recommended (see Renal Impairment as previously mentioned).
Duration of Use: Intermittent allergic rhinitis (symptoms <4 days/week or during <4 weeks) has to be treated according to the disease and its history; it can be stopped once the symptoms have disappeared and can be restarted again when symptoms reappear.
In case of persistent allergic rhinitis (symptoms >4 days/week and during >4 weeks), continuous therapy can be proposed to the patient during the period of exposure to allergens.
Clinical experience with levocetirizine 5 mg as a film-coated tablet formulation is currently available for a 6-month treatment period. For chronic urticaria and chronic allergic rhinitis, up to 1 year clinical experience is available for the racemate.
Administration: Film-Coated Tablet: Xyzal must be taken orally, swallowed whole with liquid and may be taken with or without food. It is recommended to take the daily dose in one single intake.
Oral Solution: The appropriate volume of oral solution should be measured with the oral syringe and poured in a spoon or in a glass of water. The oral solution must be taken orally immediately after dilution and may be taken with or without food.
Oral Drops: The drops should be poured in a spoon or diluted in water and taken orally. If dilution is used, it should be considered, especially for administration to children, that the volume of water to which the drops are added, needs to be adapted according to the quantity of water the patient is able to swallow. The diluted solution should be taken immediately. When counting the drops, the bottle should be held vertically (top down). In case of lack of flow of drops, if the right amount of drops has not been delivered, turn the bottle over in upright position then hold it top down again and continue counting the drops. The drops may be taken with or without food.
Overdosage
Symptoms: Symptoms of overdose may include drowsiness in adults and initially, agitation and restlessness, followed by drowsiness in children.
Treatment: There is no known specific antidote to levocetirizine. Should overdose occur, symptomatic or supportive treatment is recommended. Levocetirizine is not effectively removed by hemodialysis.
Contraindications
Hypersensitivity to levocetirizine, any piperazine derivatives or to any of the excipients of Xyzal (see Precautions).
Severe renal impairment at CrCl <10 mL/min.
Special Precautions
Alcohol: Precaution is recommended with intake of alcohol (see Interactions).
Risk of Urinary Retention: Caution should be taken in patients with predisposing factors of urinary retention (eg, spinal cord lesion, prostatic hyperplasia) as levocetirizine may increase the risk of urinary retention.
Lactose: Xyzal contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take Xyzal film-coated tablet.
Oral Solution/Drops: Methyl and Propyl Parahydroxybenzoate: The presence of methyl and propyl parahydroxybenzoate may cause allergic reactions (possibly delayed) (see Contraindications).
Oral Solution: Maltitol: Xyzal contains maltitol. Patients with rare hereditary problems of fructose intolerance should not take Xyzal oral solution.
Effects on the Ability to Drive or Operate Machinery: Comparative clinical trials have revealed no evidence that levocetirizine at the recommended dose impairs mental alertness, reactivity or the ability to drive.
Nevertheless, some patients could experience somnolence, fatigue and asthenia under therapy with levocetirizine. Therefore, patients intending to drive, engage in potentially hazardous activities or operate machinery should take into account their response to Xyzal.
Impairment of Fertility: There are no relevant data available.
Use in Children: Even if some clinical data are available in children 6 months to 12 years (see Pharmacology: Pharmacodynamics under Actions and Adverse Reactions), these data are not sufficient to support the administration of levocetirizine to infants and toddlers <2 years. Therefore, the administration of levocetirizine to infants and toddlers <2 years is not recommended.
Film-Coated Tablets: The use of the film-coated tablet is not recommended in children <6 years since this formulation does not allow for appropriate dose adaptation. It is recommended to use a pediatric formulation of levocetirizine.
Use in Pregnancy: Caution should be exercised when prescribing to pregnant women.
For levocetirizine, no clinical data on exposed pregnancies are available. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/fetal development, parturition or postnatal development.
Use in Lactation: Caution should be exercised when prescribing to lactating women. Cetirizine is excreted in human milk.
Use In Pregnancy & Lactation
Use in Pregnancy: Caution should be exercised when prescribing to pregnant women.
For levocetirizine, no clinical data on exposed pregnancies are available. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/fetal development, parturition or postnatal development.
Use in Lactation: Caution should be exercised when prescribing to lactating women. Cetirizine is excreted in human milk.
Adverse Reactions
Clinical Trial Data: In therapeutic studies in women and men 12-71 years, 15.1% of the patients in the levocetirizine 5-mg group had at least 1 adverse drug reaction compared to 11.3% in the placebo group. The 91.6% of these adverse drug reactions were mild to moderate.
In therapeutic trials, the dropout rate due to adverse events was 1% (9/935) with levocetirizine 5 mg and 1.8% (14/771) with placebo. Clinical therapeutic trials with levocetirizine included 935 subjects exposed to the drug at the recommended dose of 5 mg daily.
Adverse reactions are ranked under headings of frequency using the following convention: Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1000 to <1/100); rare (≥1/10,000 to <1/1000); very rare (<1/10,000); not known (cannot be estimated from the available data).
Nervous System Disorders: Common: Headache, somnolence.
Gastrointestinal Disorders: Common: Dry mouth. Uncommon: Abdominal pain.
General Disorders and Administration Site Conditions: Common: Fatigue. Uncommon: Asthenia.
The incidence of sedating adverse drug reactions eg, somnolence, fatigue and asthenia was altogether more common (8.1%) under levocetirizine 5 mg than under placebo (3.1%).
Oral Solution/Drops: Pediatric Patients: In 2 placebo-controlled studies in pediatric patients 6-11 months and 1 year to <6 years, 159 subjects were exposed to levocetirizine 1.25 mg daily for 2 weeks and 1.25 mg twice daily, respectively. The following incidence of adverse drug reactions was reported under levocetirizine.
Psychiatric Disorders: Common: Sleep disorders.
Nervous System Disorders: Common: Somnolence.
Gastrointestinal Disorders: Common: Diarrhea, constipation. Uncommon: Vomiting.
In children 6-12 years, double-blind placebo-controlled studies were performed where 243 children were exposed to levocetirizine 5 mg daily for variable periods ranging from <1 week to 13 weeks. The following incidence of adverse drug reactions was reported.
Nervous System Disorders: Common: Somnolence. Uncommon: Headache.
Note that even if clinical data presented in this section are available in children 6 months to 12 years, there are no sufficient data to support the administration of Xyzal to infants and toddlers <2 years.
Post-marketing Data: In addition to the adverse reactions mentioned previously and reported during clinical studies, very rare cases of the following adverse drug reactions have been reported in post-marketing experience.
Immune System Disorders: Not Known: Hypersensitivity including anaphylaxis.
Metabolism and Nutrition Disorders: Not Known: Increased weight and appetite.
Psychiatric Disorders: Not Known: Aggression, agitation, hallucination, depression, insomnia, suicidal ideation.
Nervous System Disorders: Not Known: Convulsions, paresthesia, dizziness, syncope, tremor, dysgeusia.
Eye Disorders: Not Known: Visual disturbances, blurred vision.
Ear and Labyrinth Disorders: Not Known: Vertigo.
Cardiac Disorders: Not Known: Palpitations, tachycardia.
Respiratory, Thoracic and Mediastinal Disorders: Not Known: Dyspnea.
Gastrointestinal Disorders: Not Known: Nausea, vomiting.
Hepatobiliary Disorders: Not Known: Hepatitis, abnormal liver function test.
Skin and Subcutaneous Tissue Disorders: Not Known: Angioneurotic edema, fixed drug eruption, pruritus, rash, urticaria.
Musculoskeletal and Connective Tissue Disorders: Not Known: Myalgia.
Renal and Urinary Disorders: Not Known: Dysuria, urinary retention.
General Disorders and Administration Site Conditions: Not Known: Edema.
Drug Interactions
No interaction studies have been performed with levocetirizine (including CYP3A4 inducers); studies with the racemate compound cetirizine demonstrated that there were no clinically relevant adverse interactions (with pseudoephedrine, cimetidine, ketoconazole, erythromycin, azithromycin, glipizide and diazepam).
Theophylline: A small decrease in the clearance of cetirizine (16%) was observed in a multiple-dose study with theophylline (400 mg once daily) while the disposition of theophylline was not altered by concomitant cetirizine administration.
Ritonavir: In a multiple-dose study of ritonavir (600 mg twice daily) and cetirizine (10 mg daily), the extent of exposure to cetirizine was increased by about 40% while the disposition of ritonavir was slightly altered (-11%) further to concomitant cetirizine administration.
Food: The extent of absorption of levocetirizine is not reduced with food, although the rate of absorption is decreased.
Alcohol: In sensitive patients, the simultaneous administration of cetirizine or levocetirizine and alcohol or other CNS depressants may have effects on the CNS, although it has been shown that the racemate cetirizine does not potentiate the effect of alcohol.
Storage
Film-Coated Tablet: Store at temperatures not exceeding 30°C.
Oral Drops: Store below 30°C.
Oral Solution:
Store at temperatures not exceeding 30°C.
ATC Classification
R06AE09 - levocetirizine ; Belongs to the class of piperazine derivatives used as systemic antihistamines.
Presentation/Packing
FC tab 5 mg x 30's. Soln 500 mcg/mL x 75 mL. Oral drops 5 mg/mL x 10 mL.
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