LEVOCETIRIZINE 5 MG FILM-COATED TABLETS - summary of medicine 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 doses.

4.1 Therapeutic indications

Levocetirizine 5 mg film-coated tablets are indicated in the symptomatic treatment of allergic rhinitis (including persistent allergic rhinitis) and urticaria in adults and children aged 6 ears and above.

4.2 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 (see Renal impairment below).

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 (ml/min) 0.85 for women)

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

72 x serum creatinine (mg/dl)

Dosing adjustments for patients with impaired renal function:

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.

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 paediatric 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 for more than four days a week or for more than four weeks a year), continuous therapy can be proposed to the patient duringt 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.

4.3 Contraindications

Hypersensitivity to the active substance, to cetirizine, to hydroxyzine, to any other piperazine derivatives or to any of the other excipients listed in section 6.1.

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

4.4 Special warnings and precautions for use

Precaution is recommended with concurrent intake of alcohol (see section 4.5 Interactions).

Caution should be taken in patients with predisposing factors of urinary retention (e.g. spinal cord lesion, prostatic hyperplasia) as levocetirizine may increase the risk of urinary retention.

Caution should be taken in patients with epilepsy and patients at risk of convulsion as levocetirizine may cause seizure aggravation.

Response to allergy skin tests are inhibited by antihistamines and a wash-out period (of 3 days) is required before performing them.

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

Pruritus may occur when levocetirizine is stopped even if those symptoms were not present before treatment initiation. The symptoms may resolve spontaneously. In some cases, the symptoms may be intense and may require treatment to be restarted. The symptoms should resolve when the treatment is restarted.

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 paediatric formulation of levocetirizine.

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 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.

4.6 Fertility, Pregnancy and lactation

Pregnancy

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

Breast-feeding

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.

Fertility

For levocetirizine no clinical data are available

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

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 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 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:

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%).

In two placebo-controlled studies in paediatric 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.

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.

Adverse reactions from post-marketing experience are per, System Organ Class and per frequency.

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

Respiratory, thoracic and mediastinal disorders:

Not known: dyspnoea

Gastrointestinal disorders:

Not known: nausea, vomiting, diarrhoea

Hepatobiliary disorders:

Not known: hepatitis

Renal and urinary disorders:

Not known: dysuria, urinary retention

Skin and subcutaneous tissue disorders:

Not known: angioneurotic oedema, fixed drug eruption, pruritus, rash, urticaria

Musculoskeletal, connective tissues, and bone disorders:

Not known: myalgia, arthralgia

General disorders and administration site conditions:

Not known: oedema

Investigations:

Not known: weight increased, abnormal liver function tests

Description of selected adverse reactions

After levocetirizine discontinuation, pruritus has been reported.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

5   PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: antihistamine for systemic use, piperazine derivative, ATC code: R06A E09.

Mechanism of action:

Levocetirizine, the ® 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.

Pharmacodynamic effects

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.

Clinical efficacy and safety

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, 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.

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.

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

Paediatric population

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 children below the age of 6 years, clinical safety has been established from several short- or long -term therapeutic studies:

– one clinical trial in which 29 children 2 to 6 years of age with allergic rhinitis were treated with levocetirizine 1.25 mg twice daily for 4 weeks

– one clinical trial in which 114 children 1 to 5 years of age with allergic rhinitis or chronic idiopathic urticaria were treated with levocetirizine 1.25 mg twice daily for 2 weeks

– one clinical trial in which 45 children 6 to 11 months of age with allergic rhinitis or chronic idiopathic urticaria were treated with levocetirizine 1.25 mg once daily for 2weeks

– one long-term (18 months) clinical trial in 255 levocetirizine – treated atopic subjects aged 12 to 24 months at inclusion

The safety profile was similar to that seen in the short-term studies conducted in children 1 to 5 years of age.

5.2 Pharmacokinetic properties

6   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.