SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Cetirizine Hydrochloride 5mg/5ml Solution

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Cetirizine hydrochloride 5mg/5ml For excipients, see 6.1.

3 PHARMACEUTICAL FORM

Oral Solution

Clear, colourless solution

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Adults and adolescents over 12 years of age:

Symptomatic treatment of allergic rhinitis (seasonal and perennial) associated allergic conjunctivitis, and chronic idiopathic urticaria.

Children 6-12 years:

Symptomatic treatment of allergic rhinitis (seasonal and perennial), and chronic idiopathic urticaria.

4.2 Posology and method of administration

Posology

Adults and adolescents over 12 years of age: 10ml once daily Paediatric Population

Children aged between 6 and 11 years: Either 5ml twice daily or 10ml once a day.

Children aged between 2 and 5 years: Either 2.5ml twice daily or 5ml once a day. Not recommended for children under 2 years of age.

Elderly subjects: data does not suggest that the dose needs to be reduced in elderly subjects provided that the renal function is normal. The duration of the treatment may vary depending on the symptoms.

Cetirizine is contraindicated in patients with severe renal impairment

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 excreted via renal route (see section 5.2), in cases no alternative treatment can be used,_the dosing intervals must be individualized 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:

Dosing adjustments for adult patients with impaired renal function

Group	Creatinine clearance (ml/min)	Dosage 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	Contra-indicated

In pediatric 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 his body weight.

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

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

Method of administration For oral use.

4.3 Contraindications

Cetirizine hydrochloride 10 mg Film Coated Tablets are contraindicated in

-    Patients with history of hypersensitivity to any of the constituants of the formulation , to hydroxyzine, or to piperazine derivatives

-    Patients with severe renal impairment at less than 10ml/min creatine clearance.

-    Patients with rare hereditary problems of fructose intolerance should not take Cetirizine Hydrochloride 5mg/ml Solution.

4.4 Special warnings and precautions for use

This medicinal product contains sorbitol, sodium, glycerol, methyl and propyl parahydroxy benzoates. Patients with rare hereditary problems of fructose intolerance, should not take cetirizine 5mg/5ml oral solution.

The daily dose, 10ml, of this product contains approximately 3.2mg of sodium, and excessive consumption of sodium may be harmful to people on a low sodium diet.

Glycerol can be harmful in high doses. May cause headache, stomach upset and diarrhoea.

Methyl and Propyl parahydroxy benzoate have been known to cause urticaria, but is generally a delayed reaction, such as contact dermatitis. Rarely immediate reaction with urticaria and bronchospasm.

At impaired function and renal functions, the elimination of cetirizine may be impaired. Caution should be exercised when administering cetirizine to these patients (see section 4.2 Posology, section 4.3 Contraindications).

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 is recommended with concomitant use of CNS depressants

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

In some patients, long-term treatment with cetirizine may lead to an increased risk of caries due to mouth dryness. The patients should therefore be informed about the importance of oral hygiene.

Due to the amount of some excipients in the formulation, the oral solution is not recommended in children less than 2 years.

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

Caution is recommended with the concomitant use of CNS depressants.

4.6 Fertility, pregnancy and lactation

Pregnancy

For cetirizine very rare clinical data on exposed pregnancies are available. . The data indicates no adverse effects of cetirizine on pregnancy or on the health of the foetus/new born child. To date no other relevant epidemiological data are available.

Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal / foetal development, parturition or post natal development (see 5.3). Caution should be exercised when prescribing to pregnant women.

Breast-feeding

Cetirizine is excreted in human milk at concentrations representing 0.25 to 0.90 of those measured in plasma, depending on sampling time after administration. Therefore, caution should be exercised when prescribing cetirizine to lactating women.

4.7 Effects on ability to drive and use machines

Objective measurements of driving ability, sleep latency and assembly line performance have not demonstrated any clinically relevant effects at the recommended dose of 10 mg.

Cetirizine may have minor or moderate influence on the patient’s ability to react. This should be considered when extra alertness is required e.g. when driving. Patients intending to drive, engaging in potentially hazardous activities or operating machinery should not exceed the recommended dose and should take their response to the medicinal product into account. In these sensitive patients, concurrent use with alcohol or other CNS depressants may cause additional reductions in alertness and impairment of performance.

4.8 Undesirable effects

Clinical studies have shown that cetirizine at the recommended dosage has minor undesirable 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.

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 pharmacoclinical 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	Placebo
(WHO-ART)	10 mg (n= 3260)	(n = 3061)
Body as a whole - general disorders Fatigue	1.63 %	0.95 %
Central and peripheral nervous system disorders	1.10 %	0.98 %
Dizziness Headache	7.42 %	8.07 %
Gastro-intestinal system disorders Abdominal pain	0.98 %	1.08 %
Dry mouth	2.09 %	0.82 %
Nausea	1.07 %	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	Cetirizine	Placebo
(WHO-ART)	(n=1656)	(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 effects reported during clinical studies and listed above, isolated cases of the following adverse drug reactions 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, <1/10); uncommon (>1/1,000, <1/100); rare (>1/10,000, <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

Immune system disorders:

Rare: hypersensitivity; allergic reactions; (see Skin and subcutaneous disorders)

Very rare: anaphylactic shock

Metabolism and nutrition disorders:

Not known: increased appetite

Psychiatric disorders:

Uncommon: agitation

Rare: aggression, confusion, depression, hallucination, insomnia

Very Rare: tics

Not known: suicidal ideation

Nervous system:

Uncommon: paraesthesia.

Rare: convulsions, movement disorders

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

Not Known: amnesia, memory impairment

Eye disorders:

Rare: abnormal involuntary eye movements

Very rare: accommodation disorder, blurred vision, oculogyration

Ear and labyrinth disorders:

Not known: vertigo

Cardiac disorders:

Rare: tachycardia

Gastrointestinal disorders:

Uncommon: diarrhoea

Hepatobiliary disorders

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

Skin and subcutaneous tissue disorders:

Uncommon: skin rash, pruritus Rare: urticaria

Very rare: angioedema, erythema multiforme, fixed drug eruption, angioneurotic oedema

Renal and urinary disorders:

Very rare: dysuria, enuresis, micturition difficulties

Not known: urinary retention (see section Warnings and Precautions)

General disorders and administration site conditions:

Uncommon: asthenia, malaise Rare: oedema

Investigations Rare: weight increased

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/vellowcard.

4.9 Overdose

Toxicity: There is limited experience of overdosing. 20 mg to a 2-year-old, 30 mg to a 3-year-old and 40 mg to an 11-year-old did not give any symptoms. 60 mg to a 4-year-old gave mild intoxication, 400 mg to a 14-year-old gave mild symptoms, while 400 to 500 mg to an adult gave no symptoms at all.

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 intake of at least five times the recommended daily dose are: confusion, diarrhoea, dizziness, fatigue, headache, malaise, mydriasis, pruritus, restlessness, sedation, somnolence, stupor, tachycardia, tremor and urinary retention.

Management

There is no known specific antidote to cetirizine. Should overdose occur, symptomatic or supportive measures are recommended. The patient should be kept under clinical observation for at least four hours after ingestion, and the blood pressure, heart rate and vital signs monitored until stable. In symptomatic cases, ECG should be performed.

Gastric lavage should be considered following ingestion of a short occurrence Oral activated charcoal (50 g for an adult, 10-15 g for a child) should be considered if more than 2.5 mg/kg cetirizine has been ingested within one hour,

There is no specific antidote.

Cetririzine is not effectively removed by dialysis

5.1 Pharmacodynamic properties

ATC Code: R06A E07

Pharmacotherapeutic group: Antihistamine for systemic use, piperazine derivative

Cetirizine hydrochloride is a racemate and an anti-allergic with specific histamine H1-receptor blocking characteristics.

Cetirizine inhibits cutaneous reactions in allergic individuals by VIP (Vasoactive Intestinal Polypeptide) and the P substance, neuropeptides that are considered involved in the allergic reaction. Effect is reached within 2 hours with a maximum effect after 4 hours, and remains for at least 24 hours. In allergic individuals, cetirizine inhibits the recruitment of eosinophiles after simulation with allergens and unselective histamine liberators, by a mechanism that is not primarily explained by the H1-receptor blocking characteristics of the pharmaceutical.

Cetirizine, a human metabolite of hydroxyzine, is a potent and selective antagonist of eriheral H1-receptors. In vitro receptor binding studies have shown no measurable affinity for receptors other than H1-receptors.

Studies in healthy volunteers show that cetirizine, at doses of 5 and 10mg strongly inhibits the wheal and glare 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 antihistamine effect (suppression of 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 10mg once daily improved rhinitis symptoms and did not later 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 60mg for seven days did not cause statistically significant prolongation of 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 absorbed with small inter-individual variations. Cetirizine has not been given intravenously, therefore the bioavailability, clearance and distribution volume (Vd) are unknown. Maximum plasma concentration is achieved within 1 hour and the terminal half-life is about 10 hours in adults and 6 hours in children between ages of 6-12 years. The grade of protein binding in plasma is about 93%. Cetirizine is metabolised to a small extent with a known inactive main metabolite. Cetirizine is eliminated to 60% in unchanged form via the kidneys within 96 hours. At repeated administration there is no accumulation at hand, nor is absorption or elimination affected. With impaired kidney function, the elimination is slower and the half-life is prolonged. Elimination will also be decreased in cases of hepatic impairment. There is no evidence that the pharmacokinetics of cetirizine is altered in elderly patients unless renal or hepatic function is reduced.

5.3 Preclinical safety data

Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, toxicity to reproduction, genotoxicity or carcinogenicity.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Methyl parahydroxybenzoate (E218)

Propyl parahydroxybenzoate (E216)

Sorbitol solution (70%)

Glycerol

Sodium Citrate

Citric acid

Propylene glycol

Monoammonium Glycyrrhizinate

Purified water

Flavours

Pineapple Singapore flavour (flavouring agent and propylene glycol) Sweet orange No. 1(flavouring agent and propylene glycol)

6.2 Incompatibilities

Not applicable

6.3 Shelf life

Unopened: 3 years After opening: 6 months

6.4 Special precautions for storage

No special precautions for storage

6.5    Nature and contents of container

Pack size: 200ml bottle.

Packaging: Type III amber glass bottle with Tamper proof polypropylene closure.

6.6    Special precautions for disposal

No special requirements.

7    MARKETING AUTHORISATION HOLDER

Fannin (UK) Limited 42-46 Booth Drive Park Farm South Wellingborough Northamptonshire NN8 6GT UK

8    MARKETING AUTHORISATION NUMBER(S)

PL 20417/0019

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION

12/05/2005 / 22/02/2010

10 DATE OF REVISION OF THE TEXT

19/08/2015