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Xyzal 5 mg film-coated tablets, Xyzal 0.5 mg / ml oral solution

1. Name Of The Medicinal Product

Xyzal 0.5 mg/ml oral solution

2. Qualitative And Quantitative Composition

1 ml of oral solution contains 0.5 mg levocetirizine dihydrochloride.

Excipients:

0.675 mg methyl parahydroxybenzoate/ml

0.075 mg propyl parahydroxybenzoate/ml

0.4 g maltitol/ml

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Oral solution

Clear and colorless liquid

4. Clinical Particulars

4.1 Therapeutic Indications

Symptomatic treatment of allergic rhinitis (including persistent allergic rhinitis) and urticaria.

4.2 Posology And Method Of Administration

Instruction for use

A dosing oral syringe is included in the package. 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.

Adults and adolescents 12 years and above:

The daily recommended dose is 5 mg (10 ml of solution).

Elderly:

Adjustment of the dose is recommended in elderly patients with moderate to severe renal impairment (see Patients with renal impairment below).

Children aged 6 to 12 years:

The daily recommended dose is 5 mg (10 ml of solution).

Children aged 2 to 6 years:

The daily recommended dose is 2.5 mg to be administered in 2 intakes of 1.25 mg (2.5 ml of solution twice daily).

Due to the lack of data in this population, the administration of the product to infants and toddlers aged less than 2 years is not recommended (see also section 4.4).

Adult patients with renal impairment:

The dosing intervals must be individualised according to renal function. Refer to the following table and adjust the dose as indicated. To use this dosing table, an estimate of the patient's creatinine clearance (CLcr) in ml/min is needed. The CLcr (ml/min) may be estimated from serum creatinine (mg/dl) determination using the following formula:

CLcr =

Dosing Adjustments for Patients with Impaired Renal Function:

Group

Creatinine clearance (ml/min)

Dosage and frequency

Normal

5 mg once daily

Mild

50 79

5 mg once daily

Moderate

30 49

5 mg once every 2 days

Severe

< 30

5 mg once every 3 days

End-stage renal disease - Patients undergoing dialysis

< 10-

Contra-indicated

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.

Patients with hepatic impairment:

No dose adjustment is needed in patients with solely hepatic impairment. In patients with hepatic impairment and renal impairment, adjustment of the dose is recommended (see Patients with renal impairment above).

Duration of use:

Intermittent allergic rhinitis (symptoms <4days/week or during less than 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 >4days/week and during more than 4 weeks), continuous therapy can be proposed to the patient during the period of exposure to allergens. Clinical experience with 5 mg levocetirizine as a film-coated tablet formulation is currently available for a 6-month treatment period. For chronic urticaria and chronic allergic rhinitis, up to one year's clinical experience is available for the racemate.

4.3 Contraindications

Hypersensitivity to levocetirizine, to any piperazine derivatives, to methyl parahydroxybenzoate, to propyl parahydroxybenzoate, or to any other excipients.

Severe renal impairment at less than 10 ml/min creatinine clearance.

4.4 Special Warnings And Precautions For Use

Precaution is recommended with intake of alcohol (see Interactions).

The presence of methyl parahydroxybenzoate and propyl parahydroxybenzoate may cause allergic reactions (possibly delayed).

Xyzal contains maltitol: Patients with rare hereditary problems of fructose intolerance should not take this medicine.

Due to the lack of data in this population, the administration of levocetirizine to infants and toddlers aged less than 2 years is not recommended.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

No interaction studies have been performed with levocetirizine (including no studies with 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). A small decrease in the clearance of cetirizine (16%) was observed in a multiple dose study with theophylline (400 mg once a day); while the disposition of theophylline was not altered by concomitant cetirizine administration.

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.

The extent of absorption of levocetirizine is not reduced with food, although the rate of absorption is decreased.

In sensitive patients the simultaneous administration of cetirizine or levocetirizine and alcohol or other CNS depressants may have effects on the central nervous system, although it has been shown that the racemate cetirizine does not potentiate the effect of alcohol.

4.6 Pregnancy And Lactation

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. Caution should be exercised when prescribing to pregnant or lactating women.

4.7 Effects On Ability To Drive And Use Machines

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 their response to the medicinal product into account.

4.8 Undesirable Effects

In therapeutic studies in women and men aged 12 to 71 years, 15.1% of the patients in the levocetirizine 5 mg group had at least one adverse drug reaction compared to 11.3% in the placebo group. 91.6 % of these adverse drug reactions were mild to moderate.

In therapeutic trials, the drop out rate due to adverse events was 1.0% (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. From this pooling, following incidence of adverse drug reactions were reported at rates of 1 % or greater (common: >1/100, <1/10) under levocetirizine 5 mg or placebo:

Preferred Term

(WHOART)

Placebo

(n =771)

Levocetirizine 5 mg

(n = 935)

Headache

25 (3.2 %)

24 (2.6 %)

Somnolence

11 (1.4 %)

49 (5.2 %)

Mouth dry

12 (1.6%)

24 (2.6%)

Fatigue

9 (1.2 %)

23 (2.5 %)

Further uncommon incidences of adverse reactions (uncommon >1/1000, <1/100) like asthenia or abdominal pain were observed.

The incidence of sedating adverse drug reactions such as somnolence, fatigue, and asthenia was altogether more common (8.1 %) under levocetirizine 5 mg than under placebo (3.1%).

Methyl parahydroxybenzoate and propyl parahydroxybenzoate may cause allergic reactions (possibly delayed).

In addition to the adverse reactions reported during clinical studies and listed above, very rare cases of the following adverse drug reactions have been reported in post-marketing experience.

Immune system disorders: hypersensitivity including anaphylaxis

Psychiatric disorders: aggression, agitation, hallucination, depression

Nervous system disorders: convulsion,

Eyes disorders: visual disturbances

Cardiac disorders: palpitations, tachycardia

Respiratory, thoracic, and mediastinal disorders: dyspnoea

Gastrointestinal disorders: nausea, vomiting

Hepatobiliary disorders: hepatitis

Skin and subcutaneous tissue disorders: angioneurotic oedema, fixed drug eruption, pruritus, rash, urticaria

Musculoskeletal, connective tissues, and bone disorders: myalgia

Investigations: weight increased, abnormal liver function tests

4.9 Overdose

a) Symptoms

Symptoms of overdose may include drowsiness in adults and initially agitation and restlessness, followed by drowsiness in children.

b) Management of overdoses

There is no known specific antidote to levocetirizine.

Should overdose occur, symptomatic or supportive treatment is recommended. Gastric lavage should be considered following short-term ingestion. Levocetirizine is not effectively removed by haemodialysis.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: antihistamine for systemic use, piperazine derivative.

ATC code: R06A E09.

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 half-life of 115 38 min. After single administration, levocetirizine shows a receptor occupancy of 90% at 4 hours and 57% at 24 hours.

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 randomised, controlled trials:

In a study comparing the effects of levocetirizine 5mg, desloratadine 5mg, 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 hours and lasted for 24 hours, (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 hour 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 three main inhibitory effects of levocetirizine 5 mg in the first 6 hours of pollen-induced reaction, compared with placebo in 14 adult patients: inhibition of VCAM-1 release, modulation of vascular permeability and a decrease in eosinophil recruitment.

The efficacy and safety of levocetirizine has been demonstrated in several double-blind, placebo controlled, clinical trials performed in adult patients suffering from seasonal allergic rhinitis, perennial allergic rhinitis, 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 adult patients (including 276 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 paediatric safety and efficacy of levocetirizine tablets has been studied in two placebo controlled clinical trials including patients aged 6 to 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 5mg once daily over six weeks. Treatment with levocetirizine resulted in significant decrease in pruritus severity over the first 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.

ECGs did not show relevant effects of levocetirizine on QT interval.

5.2 Pharmacokinetic Properties

The pharmacokinetics of levocetirizine are linear with dose- and time-independent with low inter-subject 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 are achieved 0.9 h after dosing. Steady state is achieved after two days. Peak concentrations are typically 270 ng/ml and 308 ng/ml following a single and a repeated 5 mg o.d. 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 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.

Biotransformation:

The extent of metabolism of levocetirizine in humans is less than 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 CYP 3A4 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 half-life in adults is 7.9 1.9 hours. The half-life is shorter in small children.

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 faeces accounts for only 12.9% of the dose. Levocetirizine is excreted both by glomerular filtration and active tubular secretion.

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 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-hour hemodialysis procedure was < 10%.

5.3 Preclinical Safety Data

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, toxicity to reproduction, genotoxicity or carcinogenicity.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Sodium acetate trihydrate (for pH adjustment)

Glacial acetic acid (for pH adjustment)

Methyl parahydroxybenzoate (E218)

Propyl parahydroxybenzoate (E216)

Glycerol 85%

Maltitol (E965)

Saccharin sodium

Tutti frutti flavor:

triacetin (E1518)

benzaldehyde

orange oil

vanilin

ethyl butyrate

orange oil concentrated

isoamyl acetate

allyl hexanoate

gamma-undecalactone

citral

geraniol

citronellol

alpha tocopherol (E307)

Purified water

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

2 years.

3 months after first opening.

6.4 Special Precautions For Storage

This medicinal product does not require any special storage conditions.

6.5 Nature And Contents Of Container

Type III 200 ml amber glass bottle closed with a white polypropylene child-resistant closure in a cardboard box also containing a graduated 10 ml oral syringe (polyethylene, polystyrene) and a patient information leaflet.

6.6 Special Precautions For Disposal And Other Handling

No special requirements.

7. Marketing Authorisation Holder

UCB Pharma Ltd

208 Bath Road

Slough

Berkshire

SL1 3WE

8. Marketing Authorisation Number(S)

PL 00039/0731

9. Date Of First Authorisation/Renewal Of The Authorisation

05/2006

10. Date Of Revision Of The Text

15/12/2010





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