Levocetirizine 5mg Film-Coated Tablets

SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Levocetirizine 5 mg film-coated tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 5 mg levocetirizine dihydrochloride.

Excipients: 60.27 mg lactose per tablet.

For a full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Film-coated tablet.

White oval film coated biconvex tablets, one side embossed with G breakline G and the other side plain. The tablet can be divided into equal halves.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Symptomatic treatment of chronic idiopathic urticaria

4.2 Posology and method of administration

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.

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 (see Patients with renal impairment below).

Children aged 6 to 12 years:

The daily recommended dose is 5 mg (1 film-coated tablet).

Children aged 2 to 6 years:

For children aged 2 to 6 years no adjusted dosage is possible with the film-coated tablet formulation. It is recommended to use a paediatric formulation of levocetirizine

Infants and toddlers aged less than 2 years :

The administration of levocetirizine is not recommended

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:

_rj _ [140-age(years)]x weight (kg)

^l-'-L-_cr — ----¹ x 0.85 for won&n ¹

72 xserum creatinine {mg! dl)

Dosing Adjustments for Patients with Impaired Renal Function:

Group	Creatinine clearance (ml/min)	Dosage and frequency
Normal	>80	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 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 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:

Clinical experience with 5 mg levocetirizine as a film-coated tablet formulation is currently available for a 6-month treatment period. For chronic urticaria, up to one year's clinical experience is available for the racemate (cetirizine).

4.3 Contraindications

Hypersensitivity to levocetirizine, to other piperazine derivatives, or to any of the excipients.

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

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

4.4 Special warnings and precautions for use

The administration of levocetirizine to infants and toddlers aged less than 2 years is not recommended. The use of the film-coated tablet formulation is not recommended in children aged 2- 6 years old since this formulation does not allow for appropriate dose adaptation. It is recommended to use a paediatric formulation of levocetirizine

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

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.

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 Fertility, pregnancy and lactation

For levocetirizine no clinical data from administration during pregnancy are available. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonic/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, reactions 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

SYSTEM ORGAN CLASS	Very common (>1/10)	Common (>1/100 to <1/10)	Uncommon (>1/1,000 to <1/100)	Very rare (<1/10,000)
Investigations				Weight Increase Abnormal liver function test
Immune system disorders				hypersensitivity including anaphylaxis
Psychiatric disorders				aggression, agitation
Nervous system disorders		Headache, somnolence		convulsion
Eye disorders				visual disturbances
Cardiac disorders				palpitations

Respiratory, thoracic and mediastinal			dyspnoea
Gastrointestinal Disorders	Dry mouth	abdominal pain	nausea
Hepatobiliary disorders			hepatitis
Skin and subcutaneous tissue disorders			angioneurotic oedema, fixed drug eruption, pruritus, rash, urticaria
Musuloskeletal, connective tissues, and bone disorders		asthenia	myalgia
General disorders and administration site conditions	fatigue

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.

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:

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.

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. 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. Preclinical results were observed only at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use.

PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Core Tablet

Microcrystalline cellulose Lactose monohydrate Silica, colloidal anhydrous Magnesium stearate Coating

Opadry Y-1-7000 consisting of: Hypromellose (E464)

Titanium dioxide (E 171) Macrogol

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

36 months

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

Blisters: Aluminium/Aluminium blisters and PVC / PVdC - Aluminium blisters

Pack Sizes

5mg film-coated tablets:

Blister: 10, 20, 21, 28, 30, 50, 90 and 100

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

Any unused product or waste material should be disposed of in accordance with local requirements.

7 MARKETING AUTHORISATION HOLDER

Glenmark Pharmaceuticals Europe Limited,

Laxmi House, 2 B Draycott Avenue,

Kenton, Middlesex HA3 0BU,

United Kingdom

8 MARKETING AUTHORISATION NUMBER(S)

PL 25258/0098

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

19/07/2012

10 DATE OF REVISION OF THE TEXT

01/07/2014