Section 2:Changes to be in line with the current QRD template

Section 4.1: Changes to be in line with the current QRD template

Section 4.2: editorial changes

Section 4.3:  addition of the contraindication in patients with hypersensitivity to ‘hydroxyzine’

Section 4.4:Changes to be in line with the current QRD template

Section 4.5:  to include levels of alcohol in blood reached during concurrent administration of cetirizine or levocetirizine and alcohol or other CNS depressants

Section 4.6: re-wording of the whole section

Section 4.8: addition of 2 side effects: arthralgia and diarrhoea and adding the reporting of side effect sub-section

Section 4.9: editorial changes

Section 5.1: editorial changes

Section 5.2: editorial changes

4.3       Contraindications

Hypersensitivity to levocetirizine, to any piperazine derivatives or to any excipients.

4.4       Special warnings and precautions for use

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.

4.8       Undesirable effects

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 1.25mg 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.

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

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

Cardiac disorders:

Not known: palpitations, tachycardia

Respiratory, thoracic, and mediastinal disorders:

Not known: dyspnoea

Gastrointestinal disorders:

Not known: nausea, vomiting

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

General disorders and administration site conditions:

Not known: oedema

Investigations:

Not known: weight increased, abnormal liver function tests

4.2       Posology and method of administration

Even if some clinical data are available in children aged 6 months to 12 years (see section 4.8, 5.1 and 5.2), these data are not sufficient to support the administration of levocetirizine to infants and toddlers aged less than 2 years. (see also section 4.4).

4.4       Special warnings and precautions for use

Even if some clinical data are available in children aged 6 months to 12 years (see section 4.8, 5.1 and 5.2), these data are not sufficient to support the administration of levocetirizine to infants and toddlers aged less than 2 years.

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). 

4.8       Undesirable effects

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 1.25mg 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. 

As stated in sections 4.2 and 4.4, please note that even if clinical data presented in this section are available in children aged 6 months to 12 years, we do not have sufficient data to support the administration of the product to infants and toddlers aged less than 2 years.

Post-marketing experience

In addition to the adverse reactions reported during clinical studies and listed above, very rare cases of the following adverse drug reactions have been reported in post-marketing experience.

• Immune system disorders: hypersensitivity including anaphylaxis
• Psychiatric disorders: aggression, agitation, hallucination, depression
• Nervous system disorders: convulsion, paraesthesia, dizziness
• Eyes disorders: visual disturbances, blurred vision
• Cardiac disorders: palpitations, tachycardia
• Respiratory, thoracic, and mediastinal disorders: dyspnoea
• Gastrointestinal disorders: nausea, vomiting
• Hepatobiliary disorders: hepatitis
• Renal and urinary disorders: dysuria
• Skin and subcutaneous tissue disorders: angioneurotic oedema, fixed drug eruption, pruritus, rash, urticaria
• Musculoskeletal, connective tissues, and bone disorders: myalgia
• Investigations: weight increased, abnormal liver function tests

Methyl parahydroxybenzoate and propyl parahydroxybenzoate may cause allergic reactions (possibly delayed).


5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties


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 2 weeks
- 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


Paediatric population:
Data from a paediatric pharmacokinetic study with oral administration of a single dose of 5 mg levocetirizine in 14 children age 6 to 11 years with body weight ranging between 20 and 40 kg show that Cmax and AUC values are about 2-fold greater than that reported in healthy adult subjects in a cross-study comparison. The mean Cmax was 450 ng/mL, occurring at a mean time of 1.2 hours, weight-normalized, total body clearance was 30% greater, and the elimination half-life 24% shorter in this paediatric population than in adults. Dedicated pharmacokinetic studies have not been conducted in paediatric patients younger than 6 years of age. A retrospective population pharmacokinetic analysis was conducted in 324 subjects (181 children 1 to 5 years of age, 18 children 6 to 11 years of age, and 124 adults 18 to 55 years of age) who received single or multiple doses of levocetirizine ranging from 1.25 mg to 30 mg. Data generated from this analysis indicated that administration of 1.25 mg once daily to children 6 months to 5 years of age is expected to result in plasma concentrations similar to those of adults receiving 5 mg once daily.

Geriatric Patients:
Limited pharmacokinetic data are available in elderly subjects. Following once daily repeat oral administration of 30 mg levocetirizine for 6 days in 9 elderly subjects (65–74 years of age), the total body clearance was approximately 33% lower compared to that in younger adults. The disposition of racemic cetirizine has been shown to be dependent on renal function rather than on age. This finding would also be applicable for levocetirizine, as levocetirizine and cetirizine are both predominantly excreted in urine. Therefore, the levocetirizine dose should be adjusted in accordance with renal function in elderly patients.

Gender:
Pharmacokinetic results for 77 patients (40 men, 37 women) were evaluated for potential effect of gender. The half-life was slightly shorter in women (7.08 ± 1.72 hr) than in men (8.62 ± 1.84 hr); however, the body weight-adjusted oral clearance in women (0.67 ± 0.16 mL/min/kg) appears to be comparable to that in men (0.59 ± 0.12 mL/min/kg). The same daily doses and dosing intervals are applicable for men and women with normal renal function.

Race:
The effect of race on levocetirizine has not been studied. As levocetirizine is primarily renally excreted, and there are no important racial differences in creatinine clearance, pharmacokinetic characteristics of levocetirizine are not expected to be different across races. No race-related differences in the kinetics of racemic cetirizine have been observed.

Hepatic impairment:
The pharmacokinetics of levocetirizine in hepatically impaired subjects have not been tested. Patients with chronic liver diseases (hepatocellular, cholestatic, and biliary cirrhosis) given 10 or 20 mg of the racemic compound cetirizine as a single dose had a 50% increase in half life along with a 40% decrease in clearance compared to healthy subjects.

Post-marketing experience

In addition to the adverse reactions reported during clinical studies and listed above, very rare cases of the following adverse drug reactions have been reported in post-marketing experience.

·        Immune system disorders: hypersensitivity including anaphylaxis

·        Psychiatric disorders: aggression, agitation, hallucination, depression

·        Nervous system disorders: convulsion, paraesthesia, dizziness

·        Eyes disorders: visual disturbances, blurred vision

·        Cardiac disorders: palpitations, tachycardia

·        Respiratory, thoracic, and mediastinal disorders: dyspnoea

·        Gastrointestinal disorders: nausea, vomiting

·        Hepatobiliary disorders: hepatitis

·        Renal and urinary disorders: dysuria

·        Skin and subcutaneous tissue disorders: angioneurotic oedema, fixed drug eruption, pruritus, rash, urticaria

·        Musculoskeletal, connective tissues, and bone disorders: myalgia

·        Investigations: weight increased, abnormal liver function tests

Methyl parahydroxybenzoate and propyl parahydroxybenzoate may cause allergic reactions (possibly delayed).

5.         PHARMACOLOGICAL PROPERTIES

5.1       Pharmacodynamic properties

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 2 weeks

- 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

Paediatric population:

Data from a paediatric pharmacokinetic study with oral administration of a single dose of 5 mg levocetirizine in 14 children age 6 to 11 years with body weight ranging between 20 and 40 kg show that Cmax and AUC values are about 2-fold greater than that reported in healthy adult subjects in a cross-study comparison. The mean Cmax was 450 ng/mL, occurring at a mean time of 1.2 hours, weight-normalized, total body clearance was 30% greater, and the elimination half-life 24% shorter in this paediatric population than in adults. Dedicated pharmacokinetic studies have not been conducted in paediatric patients younger than 6 years of age. A retrospective population pharmacokinetic analysis was conducted in 324 subjects (181 children 1 to 5 years of age, 18 children 6 to 11 years of age, and 124 adults 18 to 55 years of age) who received single or multiple doses of levocetirizine ranging from 1.25 mg to 30 mg. Data generated from this analysis indicated that administration of 1.25 mg once daily to children 6 months to 5 years of age is expected to result in plasma concentrations similar to those of adults receiving 5 mg once daily.

Geriatric Patients:

Limited pharmacokinetic data are available in elderly subjects. Following once daily repeat oral administration of 30 mg levocetirizine for 6 days in 9 elderly subjects (65–74 years of age), the total body clearance was approximately 33% lower compared to that in younger adults. The disposition of racemic cetirizine has been shown to be dependent on renal function rather than on age. This finding would also be applicable for levocetirizine, as levocetirizine and cetirizine are both predominantly excreted in urine. Therefore, the levocetirizine dose should be adjusted in accordance with renal function in elderly patients.

Gender:

Pharmacokinetic results for 77 patients (40 men, 37 women) were evaluated for potential effect of gender. The half-life was slightly shorter in women (7.08 ± 1.72 hr) than in men (8.62 ± 1.84 hr); however, the body weight-adjusted oral clearance in women (0.67 ± 0.16 mL/min/kg) appears to be comparable to that in men (0.59 ± 0.12 mL/min/kg). The same daily doses and dosing intervals are applicable for men and women with normal renal function.

Race:

The effect of race on levocetirizine has not been studied. As levocetirizine is primarily renally excreted, and there are no important racial differences in creatinine clearance, pharmacokinetic characteristics of levocetirizine are not expected to be different across races. No race-related differences in the kinetics of racemic cetirizine have been observed.

Hepatic impairment:

The pharmacokinetics of levocetirizine in hepatically impaired subjects have not been tested. Patients with chronic liver diseases (hepatocellular, cholestatic, and biliary cirrhosis) given 10 or 20 mg of the racemic compound cetirizine as a single dose had a 50% increase in half life along with a 40% decrease in clearance compared to healthy subjects.

2.              QUALITATIVE AND QUANTITATIVE COMPOSITION

Each mL, (which is equivalent to 20 drops) contains 5 mg of levocetirizine dihydrochloride.

Excipients:     0.3375 mg methyl parahydroxybenzoate/ml

                    0.0375 mg propyl parahydroxybenzoate/ml

For a full list of excipients, see section 6.1.

4.2  Posology and method of administration

Due to the lack of data in this population, the administration of the product to infants and toddlers aged less than 2 years is not recommended (see also section 4.4).

Adult patients with renal impairment:

The dosing intervals must be individualised according to renal function. 

4.3 Contraindications

Hypersensitivity to levocetirizine, to any piperazine derivatives, to methyl parahydroxybenzoate, to propyl parahydroxybenzoate, or to any other excipients.

4.4 Special warnings and precautions for use

The presence of methyl parahydroxybenzoate and propyl parahydroxybenzoate may cause allergic reactions (possibly delayed)

Due to the lack of data in this population, the administration of levocetirizine to infants and toddlers aged less than 2 years is not recommended.

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.

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.

4.8  Undesirable effects

·                Psychiatric disorders: aggression, agitation, hallucination, depression

·                Cardiac disorders: palpitations, tachycardia

·                Gastrointestinal disorders: nausea, vomiting

·                Investigations: weight increased, abnormal liver function test