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 years and above.

4.2. Posology and method of administration

Posology

Adults and adolescents 12 years and above

The daily recommended dose is 5 mg (one 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 individualized according to renal function (eGFR – estimated Glomerular Filtration Rate). 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 renal function

≥ 90

1 tablet once daily

Mildly decreased renal function

60 – <90

1 tablet once daily

Moderately decreased renal function

30 – <60

1 tablet once every 2 days

Severely decreased renal function

15 –< 30

(not requiring dialysis)

1 tablet once every 3 days

End-stage renal disease (ESRD)

< 15

(requiring dialysis treatment)

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.

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 (one 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 during 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 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.

Patients with end stage renal disease with estimated Glomerular Filtration Rate (eGFR) below 15 ml/min (requiring dialysis treatment).

4.4. Special warnings and precautions for use

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

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, 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 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 feto/ neonatal toxicity. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/fetal 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 and use machines.

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:

Preferred Term

(WHOART)

Placebo

(n = 771)

Levocetirizine 5mg

(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 to<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 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 1.25 mg daily for 2 weeks and 1.25 mg 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

Diarrhoea

0

3 (1.9 %)

Vomiting

1 (1.2 %)

1 (0.6 %)

Constipation

0

2 (1.3 %)

Nervous System Disorder

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 5 mg levoceirizine 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 5 mg (n = 243)

Headache

5 (2.1 %)

2 (0.8 %)

Somnolence

1 (0.4 %)

7 (2. 9 %)

Post-marketing experience

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, dysgueusia

• 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 suspect 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

Symptoms

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

Management of overdoses

There is no known specific antidote to levocetirizine.

Should overdose occur, symptomatic or supportive treatment is recommended. Gastric lavage may be considered shortly after ingestion of the drug.

Levocetirizine is not effectively removed by haemodialysis.