SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Ziralo Allergy Relief for Children 5mg/5ml Oral Solution

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each 5 ml spoonful contains 5mg Cetirizine hydrochloride. Each 5ml spoonful also contains the following excipients:

250 mg Propylene glycol

6.75 mg Methyl parahydroxybenzoate (E218)

0.75 mg Propyl parahydroxybenzoate (E216)

2250 mg Liquid Sorbitol (E420)

For a full list of excipients, see Section 6.1.

3    PHARMACEUTICAL FORM

Oral Solution

Clear or almost clear, colourless solution with taste and odour of banana.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

In adults and children 6 year and above:

-    Cetirizine is indicated for the relief of nasal and ocular symptoms of seasonal and perennial allergic rhinitis.

-    Cetirizine is indicated for the relief of symptoms of chronic idiopathic urticaria.

4.2    Posology and method of administration

Children aged from 6 to 12 years: 5 mg twice daily (5 ml oral solution (a full spoon twice daily).

Adults and adolescents over 12 years of age: 10 mg once daily (10 ml oral solution (2 full spoons)).

The solution can be swallowed as such.

Elderly subjects: There is no data to suggest that the dose should be reduced in elderly patients, provided that the renal function is normal.

For patients with moderate to severe renal impairment: there are no data to document the efficacy/safety ratio in patients with renal impairment. Since cetirizine is mainly eliminated via renal route (see section 5.2), in cases no alternative treatment can be used, 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 =    [140-age (vears)l x weight (kg) (x 0.85 for women)

72 x serum creatinine (mg/dl)

Dosing adjustments for adult patients with impaired renal function

Group	Creatinine clearance (ml/min)	Posology and frequency
Normal	*80	10 mg once daily
Mild	50-79	10 mg once daily
Moderate	30-49	5 mg once daily
Severe	< 30	5 mg once every 2 days
End-stage renal disease -Patients undergoing dialysis	< 10	contraindicated

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, their age and their body weight.

Patients with hepatic impairment: no dose adjustment is needed in patients with solely hepatic impairment.

Patients with hepatic and renal impairment: dose adjustment is recommended (see Patients with moderate to severe hepatic impairment above).

Method of administration:

For oral use only.

4.3 Contraindications

Cetirizine is contraindicated in patients who are hypersensitive to cetirizine, to any constituent of the product, to hydroxyzine or to any piperazine derivatives.

Cetirizine is also contraindicated in patients with severe renal impairment at less than 10 ml/min creatinine clearance.

4.4 Special warnings and precautions for use

(See also section 4.7 Effects on Ability to Drive and Use Machines).

Dosage adjustment is necessary in patients with moderate or severe renal impairment

(see section 4.2 Posology and Method of Administration).

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

Caution in epileptic patients and patients at risk of convulsions is recommended.

The use of the product is not recommended in children aged less than 6 years.

This medicinal product also contains Methyl parahydroxybenzoate and Propyl parahydroxybenzoate which may cause allergic reactions (possibly delayed).

Patients with rare hereditary problems of fructose intolerance should not take this medicinal product as it contains Liquid Sorbitol (E420).

For patients whose symptoms persist, it is advised to consult a doctor or pharmacist.

Allergy skin tests are inhibited by antihistamines and a wash-out period (of 3 days) is required before preforming them.

4.5    Interaction with other medicinal products and other forms of interaction

Due to the pharmacokinetic, pharmacodynamic and tolerance profile of cetirizine, 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 cetirizine is not reduced with food, although the rate of absorption is decreased.

Concomitant use of cetirizine with other CNS depressants should be avoided as reduction in alertness and impairment of performance may occur.

4.6    Fertility, pregnancy and lactation

Pregnancy

For cetirizine, very rare clinical data on exposed pregnancies are available. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development. Caution should be exercised when prescribing to pregnant women.

Breast-feeding

Cetirizine is excreted in human milk at concentrations representing 25% to 90% of those measured in plasma, depending on sampling time after administration. Caution therefore should be exercised when prescribing cetirizine to lactating women.

4.7 Effects on ability to drive and use machines

Studies in healthy volunteers at daily doses of 20 and 25 mg/day have not revealed adverse effects on alertness or reaction time. However, patients are advised not to exceed the recommended dose if driving or operating machinery.

Please refer also to section 4.8 Undesirable effects.

4.8 Undesirable effects

Clinical studies have shown that cetirizine at the recommended dosage has minor adverse effects on the CNS, including somnolence, fatigue, dizziness and headache. In some cases, paradoxical CNS stimulation has been reported.

Although cetirizine is a selective antagonist of peripheral H₁-receptors and is relatively free of anticholinergic activity, isolated cases of micturition difficulty, eye accommodation disorders and dry mouth have been reported. Affected patients may divide their daily dose, i.e. take as 5 mg in the morning and 5 mg in the evening.

Instances of abnormal hepatic function with elevated hepatic enzymes accompanied by elevated bilirubin have been reported. Mostly this resolves upon discontinuation of the treatment with cetirizine hydrochloride.

Clinical Trials

Double blind controlled clinical or pharmacological trials comparing cetirizine to placebo or other antihistamines at the recommended dosage (10 mg daily for cetirizine) of which quantified safety data are available, included more than 3200 subjects exposed to cetirizine.

From this pooling, the following adverse events were reported for cetirizine 10 mg in the placebo-controlled trials at rates of 1.0% or greater.

Adverse event	Cetirizine 10	Placebo
(WHO-ART)	mg (n=3260)	(n=3061)
Body as a whole - general disorders Fatigue	1.63%	0.95%
Central and peripheral nervous system disorders
Dizziness	1.10%	0.98%
Headache	7.42%	8.07%
Gastro-intestinal system disorders

Abdominal pain Dry mouth Nausea	0.98% 2.09% 1.07%	1.08% 0.82% 1.14%
Psychiatric disorders
Somnolence	9.63%	5.00%
Respiratory system disorders
Pharyngitis	1.29%	1.34%

Although statistically more common than under placebo, somnolence was mild to moderate in the majority of cases. Objective tests as demonstrated by other studies have demonstrated that usual daily activities are unaffected at the recommended daily dose in healthy young volunteers.

Adverse drug reactions at rates of 1% or greater in children aged from 6 months to 12 years, included in placebo-controlled clinical or pharmacoclinical trials are:

Adverse drug reactions (WHO-ART)	Cetirizine (n=1656)	Placebo (n=1294)
Gastro-intestinal system disorders
Diarrhoea	1.0%	0.6%
Psychiatric disorders
Somnolence	1.8%	1.4%
Respiratory system disorders
Rhinitis	1.4%	1.1%
Body as a whole - general disorders Fatigue	1.0%	0.3%

Post-marketing experience

In addition to the adverse reactions reported during clinical studies and listed above, the following undesirable effects have been reported in post-marketing experience.

Undesirable effects are described according to MedDRA System Organ Class and by estimated frequency based on post-marketing experience.

Frequencies are 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)

Blood and lymphatic system disorders

Very rare: thrombocytopenia

Not known: haemolytic anaemia

Immune system disorders:

Rare: hypersensitivity

Very rare: anaphylactic shock

Not known: bronchospasm, photosensitivity

Metabolism and nutrition disorders:

Not known: increased appetite, anorexia

Psychiatric disorders

Uncommon: agitation

Rare: aggression, confusion, depression, hallucination, insomnia Very rare: tic

Not known: suicidal ideation

Nervous system disorders

Uncommon: paraesthesia

Rare: convulsions, movement disorders

Very rare: syncope, dysgeusia, tremor, dystonia, dyskinesia

Not known: amnesia, memory impairment

Eye disorders

Very rare: accommodation disorder; blurred vision; oculogyration

Ear and labyrinth disorders:

Not known: vertigo

Cardiac disorders

Rare: tachycardia

Not known: palpitations

Gastrointestinal disorders

Uncommon: diarrhoea

Not known: vomiting, constipation

Hepatobiliary disorders:

Rare: abnormal hepatic function (increased transaminases, alkaline, phosphatase, gamma-GT and bilirubin)

Skin and subcutaneous tissue disorders Uncommon: rash, pruritus Rare: urticaria

Very rare: angioneurotic oedema, fixed drug eruption (FDE)

Not known: alopecia Renal and urinary disorders Very rare: dysuria, enuresis,

Not known: urinary retention

General disorders and administration site conditions

Uncommon: asthenia, malaise

Rare: oedema

Investigations

Rare: weight increase

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 the Yellow Card Scheme at www.mhra.gov.uk/yellowcard.

4.9 Overdose

a) Symptoms

Symptoms observed after an overdose of cetirizine 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.

b) Management

There is no known specific antidote to cetirizine.

Should overdose occur, symptomatic or supportive treatment is recommended. Gastric lavage should be considered following ingestion of a short occurrence.

Cetirizine is not effectively removed by dialysis.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic classification: Piperazine derivatives

R06A E07 (ATC classification system)

Cetirizine, a human metabolite of hydroxyzine, is a potent antihistamine, selective H1 receptor antagonist. The histamine-mediated ‘early’ phase of the allergic reaction is inhibited by cetirizine, which also reduces the migration of inflammatory cells and the release of mediators associated with the ‘late’ allergic responses. Effects on other receptors are negligible and consequently cetirizine is unlikely to cause undesirable anti-cholinergic and anti-serotonin effects. At the recommended therapeutic dose of 10 mg daily, impairment of CNS function has not been found to be greater than with the placebo.

In addition to its anti-H1 effect, cetirizine was shown to display anti-allergic activities: at a dose of 10 mg once or twice daily, it inhibits the late phase recruitment of eosinophils, in the skin and conjunctiva of atopic subjects submitted to allergen challenge.

Studies in healthy volunteers show that cetirizine, at doses of 5 mg and 10 mg strongly inhibits the wheal and flare reactions induced by very high concentrations of histamine into the skin, but the correlation with efficacy is not established.

In a 35-day study in children aged 5 to 12, no tolerance to the antihistaminic effect (suppression of the wheal and flare) of cetirizine was found. When a treatment with cetirizine is stopped after repeated administration, the skin recovers its normal reactivity to histamine within 3 days.

In a six-week, placebo-controlled study of 186 patients with allergic rhinitis and concomitant mild to moderate asthma, cetirizine 10 mg once daily improved rhinitis symptoms and did not alter pulmonary function. This study supports the safety of administering cetirizine to allergic patients with mild to moderate asthma.

In a placebo-controlled study, cetirizine given at the high daily dose of 60 mg for seven days did not cause statistically significant prolongation of the QT interval.

At the recommended dosage, cetirizine has demonstrated that it improves the quality of life of patients with perennial and seasonal allergic rhinitis.

5.2 Pharmacokinetic properties

Cetirizine is rapidly absorbed from the gastrointestinal tract; absorption is not reduced by food, though the rate may be decreased slightly. Peak blood levels in the order of 0.3 micrograms/ml are attained between 30 and 60 minutes following administration of a 10 mg oral dose of cetirizine. Apparent plasma clearance is greater in children than in adults: the terminal elimination half-life in healthy adult volunteers ranges between 6.7 - 10.7 hours; in children 6.1 - 7.1 hours; and in children aged under 4 years 5.55 hours. Cetirizine is mainly excreted unchanged in the urine (approximately 70% over 5 days compared with 10% in the faeces). The half-life is increased in renal dysfunction: half lives of 19 and 21 hours in patients with mild to moderate renal impairment respectively have been reported. This may have implications for elderly patients. Cetirizine binds strongly to plasma proteins.

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

Propylene glycol

Glycerol

Methyl parahydroxybenzoate (E218)

Propyl parahydroxybenzoate (E216)

Sodium acetate Acetic acid Saccharin sodium Liquid Sorbitol (E420)

Banana flavour (contains ethanol) Purified water

6.2    Incompatibilities

None known.

6.3    Shelf life

Shelf life before opening - 36 months Shelf life after opening - 6    months

6.4    Special precautions for    storage

Do not store above 25°C.

6.5    Nature and contents of container

Type III amber glass bottles with a tamper evident screw cap having a polypropylene outer layer and a polyethylene inner layer.

Polystyrene/polyethylene measuring device.

60ml

6.6    Special precautions for disposal

None.

7 MARKETING AUTHORISATION HOLDER

Pinewood Laboratories Limited,

Ballymacarbry,

Clonmel,

Co. Tipperary,

Ireland.

8    MARKETING AUTHORISATION NUMBER(S)

PL 04917/0140

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

08/10/2015

10    DATE OF REVISION OF THE TEXT

30/09/2016