LEVONEX
(Film Coated Tablet 5 mg)
The active ingredient of LEVONEX is Levocetirizine 5 mg film-coated tablets. Antihistamine for systemic use, piperazine derivative.
PRESENTATION
Each film-coated tablet contains 5 mg levocetirizine hydrochloride.
PHARMACOLOGICAL PROPERTIES
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.
Pharmacodynamics studies in healthy volunteers demonstrate that, at half the dose, levocetirizine has comparable activity to cetirizine, both in the skin and in the nose.
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.
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.
SPECIAL POPULATION
Pharmacokinetic / Pharmacodynamics Relationship
The action on histamine-induced skin reactions is out of phase with the plasma concentrations.
Preclinical Safety Data
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction
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 antipyrine, azithromycin, cimetidine, diazepam, erythromycin, glipizide, ketoconazole and pseudoephedrine). 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 concurrent administration of cetirizine or levocetirizine and alcohol or other CNS depressants may cause additional reductions in alertness and impairment of performance.
CLINICAL PARTICULARS
Therapeutic indications
Levocetirizine 5 mg film-coated tablets are indicated in the symptomatic treatment of allergic rhinitis (including persistent allergic rhinitis) and urticarial in adults and children aged 6 ears and above.
POSOLOGY AND METHOD OF ADMINISTRATION
Posology
Adults and adolescents 12 years and above: The daily recommended dose is 5 mg (1 film-coated tablet).
Elderly: Adjustment of the dose is recommended in elderly patients with moderate to severe renal impairment.
Renal impairment: The dosing intervals must be individualized 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:
Dosing adjustments for patients with impaired renal function:
Group |
Creatinine clearance (ml/min) |
Dosage and frequency |
Normal |
80 |
1 tablet once daily |
Mild |
50 – 79 |
1 tablet once daily |
Moderate |
30 – 49 |
1 tablet once every 2 days |
Severe |
< 30 |
1 tablet 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.
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 Renal impairment above).
Paediatric population
Children aged 6 to 12 years: The daily recommended dose is 5 mg (1 film-coated tablet).
For children aged 2 to 6 years no adjusted dosage is possible with the film-coated tablet formulation. It is recommended to use a pediatric formulation of levocetirizine.
Method of Administration
The film-coated tablet 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.
Duration of use:
Intermittent allergic rhinitis (symptoms experienced for less than four days a week or for less than four weeks a year) 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 experienced more than four day a week or for more than four weeks a year), continuous therapy can be proposed to the patient throughout the period of exposure to allergens.
There is clinical experience with the use of levocetirizine for treatment periods of at least 6 months. In chronic urticaria and chronic allergic rhinitis, there is clinical experience of the use of cetirizine (racemate) for up to one year.
SIDE EFFECTS/UNDESIRABLE EFFECTS
Clinical studies
Adults and adolescents above 12 years of age:
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 dropout 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 medicinal product 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 to <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%).
Paediatric population
In two placebo-controlled studies in pediatric patients aged 6-11 months and aged 1 year to less than 6 years, 159 subjects were exposed to levocetirizine at the dose of 1.25mg daily for 2 weeks and 1.25mg twice daily respectively. The following incidence of adverse drug reactions was reported at rates of 1% or greater under levocetirizine or placebo.
System Organ Class and Preferred Term |
Placebo (n=83) |
Levocetirizine (n=159) |
Gastrointestinal disorders |
||
Diarrhea |
0 |
3(1.9%) |
Vomiting |
1(1.2%) |
1(0.6%) |
Constipation |
0 |
2(1.3%) |
Nervous system disorders |
||
Somnolence |
2(2.4%) |
3(1.9%) |
Psychiatric disorders |
||
Sleep disorder |
0 |
2(1.3%) |
In children aged 6-12 years double blind placebo controlled studies were performed where 243 children were exposed to 5mg levocetirizine daily for variable periods ranging from less than 1 week to 13 weeks. The following incidence of adverse drug reactions was reported at rates of 1% or greater under levocetirizine or placebo.
Preferred Term |
Placebo (n=240) |
Levocetirizine 5mg (n=243) |
Headache |
5(2.1%) |
2(0.8%) |
Somnolence |
1(0.4%) |
7(2.9%) |
Post-marketing experience
The frequency is defined as follows:
Very common (≥1/10);
Common (≥1/100 to <1/10);
Uncommon (≥1/1,000 to <1/100);
Rare (≥1/10,000 to <1/1,000);
Very rare (≤1/10,000) Not known (cannot be estimated from the available data)
Immune system disorders: Not known: hypersensitivity including anaphylaxis
Metabolism and nutrition disorders: Not known: increased appetite
Psychiatric disorders: Not known: aggression, agitation, hallucination, depression, insomnia, suicidal ideation, nightmare
Nervous system disorders: Not known: convulsion, paraesthesia, dizziness, syncope, tremor, dysgeusia
Ear and labyrinth disorders: Not known: vertigo
Eyes disorders: Not known: visual disturbances, blurred vision, oculogyration
Cardiac disorders: Not known: palpitations, tachycardia
Gastrointestinal disorders:
Not known: nausea, vomiting, diarrhea
Hepatobiliary disorders:
Not known: hepatitis
Renal and urinary disorders:
Not known: dysuria, urinary retention
Skin and subcutaneous tissue disorders: Not known: angioneurotic edema, fixed drug eruption, pruritus, rash, urticaria
Musculoskeletal, connective tissues, and bone disorders: Not known: myalgia, arthralgia
General disorders and administration site conditions: Not known: edema
Overdose
Symptoms
Symptoms of overdose may include drowsiness in adults. In children, agitation and restlessness may initially occur, followed by drowsiness in children.
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 shortly after ingestion of the drug. Levocetirizine is not effectively removed by hemodialysis.
SPECIAL WARNINGS AND PRECAUTIONS FOR USE
Paediatric Population
The use of the film-coated tablet formulation is not recommended in children aged less than 6 years since this formulation does not allow for appropriate dose adaptation. It is recommended to use a pediatric formulation of levocetirizine
FERTILITY, PREGNANCY AND LACTATION
There are no or limited amount of data (less than 300 pregnancy outcomes) from the use of levocetirizine in pregnant women. However, for cetirizine, the racemate of levocetirizine, a large amount of data (more than 1000 pregnancy outcomes) on pregnant women indicate no malformative or foeto/ neonatal toxicity.
Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see section 5.3).
The use of Levocetirizine may be considered during pregnancy, if necessary
Cetirizine, the racemate of levocetirizine, has been shown to be excreted in human. Therefore, the excretion of levocetirizine in human milk is likely. Adverse reactions associated with levocetirizine may be observed in breastfed infants. Therefore, caution should be exercised when prescribing levocetirizine to lactating women.
For levocetirizine no clinical data are available
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.
CONTRAINDICATIONS