Levocetirizine Dihydrochloride 5 Mg Film-Coated Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Levocetirizine dihydrochloride 5 mg Film-coated Tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each film-coated tablet contains 5 mg levocetirizine dihydrochloride (equivalent to 4.2 mg of levocetirizine).
Excipient: each film-coated tablet contains 64.0 mg lactose monohydrate.
For a full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Film-coated tablet.
White to off-white, oval, biconvex film-coated tablets, debossed with ‘L9CZ’ on one side and ‘5’ on the other side.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Levocetirizine is indicated for:
- the relief of nasal and ocular symptoms of seasonal and perennial
allergic rhinitis;
- the relief of symptoms of chronic idiopathic urticaria.
4.2 Posology and method of administration
The film-coated tablet must be taken orally, swallowed whole with liquid and may be taken with or without food.
Adults and adolescents 12 years and above
The daily recommended dose is 5 mg (one film-coated tablet) once daily.
Children aged 6 to 12 years
The daily recommended dose is 5 mg (one film-coated tablet) daily.
Levocetirizine is not recommended for use in children below age 6 due to insufficient data on safety and efficacy.
Elderly
For the time being, there is no data to suggest that the dose needs to be reduced in elderly patients provided that the renal function is normal.
Patients with moderate to severe renal impairment: there are no data to document the efficacy/safety ratio in patients with renal impairment. Since levocetirizine is mainly excreted via renal route (see section 5.2), in cases no alternative treatment can be used, 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:
CL = \l4-0-age(years)]x\veight{kg) ( „ . %
LJ-a 1-il-§—for women)
12 x serum creatinine {mg I dJ) '
Dosing adjustments for adult patients with impaired renal function:
|
Group |
Creatinine clearance (ml/min) |
Dosage and freauency |
|
Normal |
> 80 |
One tablet daily |
|
Mild |
50 - 79 |
One tablet daily |
|
Moderate |
30 - 49 |
One tablet every two days |
|
Severe |
< 30 |
One tablet every three days |
|
End-stage renal disease - patients undergoing dialysis |
< 10 |
Contra-indicated |
In paediatric 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, his age and his body weight.
Patients with hepatic impairment
No dose adjustment is needed in patients with solely hepatic impairment.
Patients with hepatic impairment and renal impairment
Dose adjustment is recommended (see Patients with moderate to severe renal impairment above).
4.3 Contraindications
Hypersensitivity to levocetirizine, to any of the excipients, to hydroxyzine or to any piperazine derivatives.
Patients with severe renal impairment at less than 10 ml/min creatinine clearance.
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose- galactose malabsorption should not take levocetirizine film-coated tablets.
4.4 Special warnings and precautions for use
Do not exceed the stated dose.
The use of levocetirizine dihydrochloride is not recommended in children aged less than 6 years since the currently available film-coated tablets do not yet allow dose adaptation.
At therapeutic doses, no clinically significant interactions have been demonstrated with alcohol (for a blood alcohol level of 0.5 g/L). Nevertheless, precaution is recommended if alcohol is taken concomitantly.
Caution in epileptic patients and patients at risk of convulsions is recommended.
4.5 Interaction with other medicinal products and other forms of interaction
Due to the pharmacokinetic, pharmacodynamic and tolerance profile of levocetirizine, no interactions are expected with this antihistamine. Actually, neither pharmacodynamic nor significant pharmacokinetic interaction was reported in drug-drug interactions studies performed, notably with pseudoephedrine or theophylline (400 mg/day).
The extent of absorption of levocetirizine is not reduced with food, although the rate of absorption is decreased.
4.6 Pregnancy and lactation
Very rare 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 breast feeding women because levocetirizine passes into breast milk.
4.7 Effects on ability to drive and use machines
Objective measurements of driving ability, sleep latency and assembly line performance have not demonstrated any clinically relevant effects at the recommended dose of 5 mg.
Patients intending to drive, engaging in potentially hazardous activities or operating machinery should not exceed the recommended dose and should take their response to the medicinal product into account. In these sensitive patients, concurrent use with alcohol or other CNS depressants may cause additional reductions in alertness and impairment of performance.
4.8 Undesirable effects
The frequency of undesirable effects has been defined as: 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).
|
Common |
Uncommon |
Rare |
Very rare | |
|
Blood and lymphatic system disorders |
Thrombocytopenia | |||
|
Immune system disorders |
Hypersensitivity |
Anaphylactic shock | ||
|
Psychiatric disorders |
Somnolence |
Agitation |
Aggression Confusion Depression Hallucination Insomnia |
Tic |
|
Nervous system disorders |
Dizziness Headache |
Paraesthesia |
Convulsions Movement disorders |
Dysgeusia Syncope Tremor Dystonia Dyskinesia |
|
Eye disorders |
Accommodation disorder Blurred vision Oculogyration | |||
|
Cardiac disorders |
Tachycardia | |||
|
Respiratory, thoracic and mediastinal disorders |
Pharyngitis Rhinitis* | |||
|
Gastrointestinal disorders |
Abdominal pain Dry mouth Nausea |
Diarrhoea | ||
|
Hepatobiliary disorders |
Hepatic function abnormal (increased transaminases, alkaline phosphatase, y-GT and bilirubin) | |||
|
Skin and subcutaneous tissue disorders |
Pruritus Rash |
Urticaria |
Angioneurotic oedema Fixed drug eruption | |
|
Renal and urinary disorders |
Dysuria Enuresis |
|
General disorders and administration site conditions |
Fatigue |
Asthenia Malaise |
Oedema | |
|
Investigations |
Weight increased |
* in children
4.9 Overdose
Symptoms
Symptoms observed after an overdose of levocetirizine are mainly associated with CNS effects or with effects that could suggest an anticholinergic effect.
Adverse events reported after an intake of at least 5 times the recommended daily dose are: confusion, diarrhoea, dizziness, fatigue, headache, malaise, mydriasis, pruritus, restlessness, sedation, somnolence, stupor, tachycardia, tremor and urinary retention.
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 ingestion of a short occurrence.
Levocetirizine is not effectively removed by dialysis.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antihistamine for systemic use, piperazine derivatives, 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.
Levocetirizine inhibits the histamine-mediated early phase of the allergic reaction and also reduces the migration of certain inflammatory cells and the release of certain mediators associated with the late allergic response.
The efficacy and safety of levocetirizine has been demonstrated in several doubleblind, placebo controlled, clinical trials performed in adult patients suffering from seasonal allergic rhinitis or perennial allergic rhinitis.
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.
Pharmacokinetic / pharmacodynamic relationship
5 mg levocetirizine provides a similar pattern of inhibition of histamine-induced wheal and flare as 10 mg cetirizine. As for cetirizine, the action on histamine-induced skin reactions was 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. 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.
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 mean apparent total body clearance 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.
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.
5.3 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.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Tablet core Lactose monohydrate Cellulose microcrystalline Magnesium stearate (E572)
Film-coating Hypromellose (E464)
Titanium dioxide (E171)
Macrogol 400
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
36 months
6.4 Special precautions for storage
Store in the original package in order to protect from moisture
6.5 Nature and contents of container
PVC/PVDC:Al blisters or oPA/Al/PVC:Al blisters
Pack sizes:
Blisters containing 7, 10, 14, 15, 20, 21, 28, 30, 40, 50, 56, 60, 70, 90, 100, 112 or 120 tablets
Unit dose blisters containing: 30x1 tablets
Not all pack sizes may be marketed.
Special precautions for disposal
6.6
No special requirements.
7 MARKETING AUTHORISATION HOLDER
Hexal AG Industriestrasse 25,
D-83607, Holzkirchen,
Germany
8 MARKETING AUTHORISATION NUMBER(S)
PL 10880/0135
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
14/10/2009
10 DATE OF REVISION OF THE TEXT
15/04/2011