SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Teva Cetirizine Hydrochloride 1 mg/ml oral solution.

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each 1 ml of solution contains 1 mg of cetirizine hydrochloride.

Excipients with known effects:

This product also contains:

1ml of solution contains 200 mg of glycerol 1 ml of solution contains 49 mg of__propylene glycol

1 ml of solution contains 450 mg of Liquid non crystallising sorbital (sorbital 70% solution)

For the full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM Oral solution.

Clear colourless solution with a banana odour.

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.

Children 2-6 years

Symptomatic treatment of seasonal allergic rhinitis

4.2 Posology and method of administration

Adults and adolescents over 12 years of age: 2 x 5 mg (5 ml) once daily.

If drowsiness occurs, the solution can be administered in the evening.

Children 6-12 years:

2 x 5 mg (5 ml) once daily or 5 mg (5 ml) taken twice daily (morning and evening).

Children 2-6years or weighing less than 30 Kg:

5 mg (5 ml) taken once daily or 2.5 mg (2.5 ml) twice daily.

At present there is insufficient clinical data to recommend the use of cetirizine in children under 2 years of age.

Older people : data do not suggest that the dose needs to be reduced in older people provided that the renal function is normal.

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:

CLcr =    [140 -age years] 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	Dosage and
frequency	(ml/min)	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 -	< 10	Contra-indicated
Patients undergoing
dialysis

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, his 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: adjustment of the dose is recommended (see subsection Patients with moderate and severe renal impairment above).

4.3 Contraindications

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

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

Patients with rare hereditary problems of fructose intolerance should not take cetirizine mg/ml oral solution.

4.4 Special warnings and precautions for use

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.

Methyl parahydroxybenzoate and propyl parahydroxybenzoate included in the 10 mg/ml oral drops and in the 1 mg/ml oral solution may cause allergic reactions (possibly delayed).

Patients with rare hereditary problems of fructose intolerance should not take cetirizine 1mg/ml oral solution

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

Paediatric population

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

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.

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,

embryo/foetal development, parturition or post natal development (see section 5.3). Caution should be exercised when prescribing to pregnant women.

Breast-feeding Cetirizine is excreted into human milk at concentrations representing 25% to 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.

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 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 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.

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.

Clinical trials

Double blind controlled clinical 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 reactions were reported for cetirizine 10 mg in the placebo-controlled trials at rates of 1.0 % or greater:

Adverse reactions (WHO-ART)	Cetirizine 10 mg (n= 3260)	Placebo (n = 3061)
Body as a whole - general disorders Fatigue	1.63 %	0.95 %

Central and peripheral nervous system disorders Dizziness Headache	1.10 % 7.42 %	0.98 % 8.07 %
Gastrointestinal system disorders Abdominal pain	0.98 %	1.08 %
Dry mouth	2.09 %	0.82 %
Nausea	1.07 %	1.14 %
Psychiatric disorders		5.00 %
Somnolence	9.63 %
Respiratory system disorders		1.34 %
Pharyngitis	1.29 %

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

Adverse reactions	Cetirizine	Placebo
(WHO-ART)	(n=1656)	(n =1294)
Gastrointestinal 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 disorders:

Very rare : thrombocytopenia

Immune system disorders:

Rare:    hypersensitivity

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 disorders:

Uncommon : paraesthesia Rare : convulsions

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

Gastrointestinal disorders Uncommon:    diarrhea

Hepatobiliary disorders

Rare:    hepatic function abnormal (increased transaminases, alkaline

phosphatase, y-GT and bilirubin)

Skin and subcutaneous tissue disorders Uncommon:    pruritus, rash

Rare:    urticaria

Very rare:    angioneurotic oedema, fixed drug eruption

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 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/yellowcard

4.9 Overdose

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.

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 group: Antihistamines for systemic use, piperazine derivatives

ATC code: R06A E07

Pharmacotherapeutic group: Antihistamines for systemic use, piperazine derivatives ATC code: R06A E07

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

Cetirizine inhibits cutaneous reactions in allergic individuals through VIP (Vasoactive Intestinal Polypeptide) and substance P, neuropeptides that are considered to be 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 eosinophils after stimulation with allergens and non selective histamine liberators, by a mechanism that is not primarily explained by the H₁-receptor blocking characteristics of the pharmaceutical.

Studies in healthy volunteers show that cetirizine, at doses of 5 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 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 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 volume of distribution (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 the age of 6-12 years. The grade of protein binding in plasma is about 93%. Cetrizine is metabolised to a small extent with a known inactive main metabolite. 60% of a dose of cetirizine is eliminated in unchanged form via the kidneys within 96 hours. Repeated administration does not lead to any accumulation, nor is the absorption or elimination affected. In cases of 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.

Special populations

Older people : Following a single 10 mg oral dose, half-life increased by about 50 % and clearance decreased by 40 % in 16 older people compared to the normal subjects. The decrease in cetirizine clearance in these older volunteers appeared to be related to their decreased renal function.

Children, infants and toddlers: The half-life of cetirizine was about 6 hours in children of 6-12 years and 5 hours in children 2-6 years. In infants and toddlers aged 6 to 24 months, it is reduced to 3.1 hours

Renally impaired patients: The pharmacokinetics of the drug were similar in patients with mild impairment (creatinine clearance higher than 40 ml/min) and healthy volunteers. Patients with moderate renal impairment had a 3-fold increase in half-life and 70 % decrease in clearance compared to healthy volunteers.

Patients on hemodialysis (creatinine clearance less than 7 ml/min) given a single oral 10 mg dose of cetirizine had a 3-fold increase in half-life and a 70 % decrease in clearance compared to normals.

Cetirizine was poorly cleared by haemodialysis. Dosing adjustment is necessary in patients with moderate or severe renal impairment (see section 4.2).

Hepatically impaired patients: Patients with chronic liver diseases (hepatocellular, cholestatic, and

biliary cirrhosis) given 10 or 20 mg of cetirizine as a single dose had a 50 % increase in half-life along with a 40 % decrease in clearance compared to healthy subjects.

Dosing adjustment is only necessary in hepatically impaired patients if concomitant renal impairment is present.

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

Glycerol Propylene glycol Sorbitol 70% solution Methylparaben Propylparaben Sodium acetate Acetic acid glacial Saccharin sodium Banana flavour Purified water

6.2    Incompatibilities

Not applicable.

6.3    Shelf life

2 years.

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

Pack sizes: 75, 150 and 200 ml fill bottles.

Amber glass bottle, with child-resistant polypropylene screw cap incorporating a tamper evident seal (yellow polyethylene).

Measuring device: 5 ml plastic PP measuring spoon graduated at 2.5 ml Not all pack sizes may be marketed

6.6    Special precautions for disposal

No special requirements.

7    MARKETING AUTHORISATION HOLDER

Teva Pharma B.V.

Swensweg 5,

2031 GA Haarlem,

The Netherlands

8    MARKETING AUTHORISATION NUMBER(S)

PL 14776/00072

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

12/11/2007

10    DATE OF REVISION OF THE TEXT

29/07/2015