Zirtene 10 mg film-coated tablets

4.2 Posology and method of administration

Posology

Adults 10 mg once daily (1 tablet)

Special Population

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

4.8 Undesirable effects

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

Adverse event reaction (WHO-ART)	Cetirizine 10 mg (n= 3260)	Placebo (n = 3061)
General disorders and administration site conditions   Fatigue	1.63 %	0.95 %
Nervous system disorders   Dizziness Headache	1.10 % 7.42 %	0.98 % 8.07 %
Gastro-intestinal  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, thoracic and mediastinal disorders   Pharyngitis	1.29 %	1.34 %

Post-marketing experience

In addition to the adverse reactions reported during clinical studies and listed above, 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 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, nightmare

Nervous system disorders:
Uncommon: paraesthesia
Rare: convulsions
Very rare: dysgeusia, syncope, 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

Gastro-intestinal disorders:
Uncommon: diarrhoea

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

Skin and subcutaneous tissue disorders:
Uncommon: pruritus, rash
Rare: urticaria
Very rare: angioneurotic oedema, fixed drug eruption
Not known: acute generalized exanthematous pustulosis

Musculoskeletal and connective tissue disorders
Not known: arthralgia

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

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 may be considered shortly afterfollowing ingestion of a short occurrencethe drug.

Cetirizine is not effectively removed by dialysis.

 

4.2 Posology and method of administration

Posology

Children aged from 6 to 12 years: 5 mg twice daily (For this dosing regimen; a different formulation should be used).

Adults and adolescents over 12 years of age: 10 mg once daily (1 tablet)

Special Population

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

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, the child’s age and 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).

Paediatric population

The tablet formulation should not be used in children under 6 years of age as it does not allow the necessary dose adjustments.

Children aged from 6 to 12 years: 5 mg twice daily (For this dosing regimen; a different formulation should be used).

Adolescents over 12 years of age: 10 mg once daily (1 tablet)

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, the child’s age and body weight.

Method of administration
The tablets need to be swallowed with a glass of liquid.


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

Response to Aallergy 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 cetirizine film-coated tablets.

Pruritus and/or urticaria may occur when cetirizine is stopped, even if those symptoms were not present before treatment initiation. 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 cetirizine.

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.

In sensitive patients, the concurrent use of alcohol or other CNS depressants may cause additional reductions in alertness and impairment of performance, although cetirizine does not potentiate the effect of alcohol (0.5 g/L blood levels).

4.6 Fertility, pregnancy and lactation

Pregnancy
For cetirizine prospectively collected data on pregnancy outcomes do not suggest potential for maternal or foetal/embryonic toxicity above background rates.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/fetalfoetal 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. Therefore, caution should be exercised when prescribing cetirizine to lactating women.

Fertility

Limited data is available on human fertility but no safety concern has been identified.

Animal data show no safety concern for human reproduction.


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.

However, patients who experience somnolence should refrain from driving, engaging in potentially hazardous activities or operating machinery.

 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

Overview

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 dihydrochloride.

Clinical trials
Listing of ADRs

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 (WHO-ART)	Cetirizine 10 mg (n= 3260)	Placebo (n = 3061)
Body as a whole gGeneral disorders and administration site conditions   Fatigue	1.63 %	0.95 %
Central and peripheral nNervous system disorders   Dizziness Headache	1.10 % 7.42 %	0.98 % 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 thoracic and mediastinal 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.

Paediatric population

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, thoracic and mediastinal system disorders   Rhinitis	1.4 %	1.1 %
Body as a whole gGeneral disorders and administration site conditions   Fatigue	1.0 %	0.3 %

Eye disorders:
Very rare: accommodation disorder, blurred vision, oculogyrationic crisis

Description of selected adverse reactions
After discontinuation of cetirizine, pruritus (intense itching) and/or urticaria have 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 suspected adverse reactions via HPRA Pharmacovigilance, Earlsfort Terrace, IRL – Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website: www.hpra.ie; E-mail: medsafety@hpra.ie.

5. PHARMACOLOGICAL PROPERTIES

5.1  Pharmacodynamic properties

Pharmacotherapeutic group: Antihistamine for systemic use,  Ppiperazine derivatives, ATC code: R06A E07

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

Pharmacodynamic effects
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.

Clinical efficacy and safety
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.

Paediatric population
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.

5.2 Pharmacokinetic properties

Absorption
The steady - state peak plasma concentrations is approximately 300 ng/ml and is achieved within 1.0 +/- 0.5 h. The distribution of pharmacokinetic parameters such as peak plasma concentration (Cmax) and area under curve (AUC), is unimodal. No accumulation is observed for cetirizine following daily doses of 10 mg for 10 days.

The extent of absorption of cetirizine is not reduced with food, although the rate of absorption is decreased.
The extent of bioavailability is similar when cetirizine is given as solutions, capsules or tablets.

Distribution
The distribution of pharmacokinetic parameters such as peak plasma concentration (Cmax) and area under curve (AUC), is unimodal in human volunteers.
The extent of bioavailability is similar when cetirizine is given as solutions, capsules or tablets.

The apparent volume of distribution is 0.50 l/kg. Plasma protein binding of cetirizine is 93 0.3 %. Cetirizine does not modify the protein binding of warfarin.

Biotransformation
Cetirizine does not undergo extensive first pass metabolism.

Elimination
The terminal half-life is approximately 10 hours. and Nno accumulation is observed for cetirizine following daily doses of 10 mg for 10 days. About two thirds of the dose are excreted unchanged in urine. The terminal half-life is approximately 10 hours.

Linearity/non-linearity
Cetirizine exhibits linear kinetics over the range of 5 to 60 mg.

Special populations

Renally impairmented 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 impairedment 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

Older people: Following a single 10 mg oral dose, half-life increased by about 50 % and clearance decreased by 40 % in 16 older subjects 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 toddlersPaediatric population: 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 normal. 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.

 

Extensive updates to the SmPC in line with the reference product, QRD template and editorial changes.

Extensive updates to SPC in line withe Core Safety Profile for cetirizine following the PSUR Worksharing procedures FI/H/PSUR/0019/001 and FI/H/PSUR/0019/002 and current QRD template.

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

One film-coated tablet contains Cetirizine dihydrochloride 10 mg

10mg cetirizine dihydrochloride
Excipients: Each tablet contains 74.3mg lactose monohydrate.one film-coated tablet contains 74.3mg lactose-monohydrate
For a full list of excipients, see section 6.1.

 

3. PHARMACEUTICAL FORM

 

 

Film-coated tablet. (tablet)

Film-coated tablets

 

 

 

White, capsule shaped, film coated tablet with breakline and marked ‘CZ’ and ‘10’ on one side and
marked ‘G’ on the reverse.
The breakline is to facilitate breaking for ease of swallowing and not to divide into equal doses.

4.1 Therapeutic indications

Cetirizine is indicated for the management of seasonal allergic rhinitis (hay fever), perennial rhinitis, urticaria and senile pruritus.

In adults and paediatric patients 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

Adults, the elderly and children aged 6 years and over:
The recommended dose is 10 mg once daily.
For patients who experience mild side effects the dosage should be halved and taken twice daily.
For patients with moderate to severe renal impairment: 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 creatine clearance (CLcr) in ml/min is needed. The CLcr (ml/min) may be estimated from serum creatine (mg/dl), determination using the following formula:
[140-age(years)] x weight (kg)
Clcr =_____________________________ (x 0.85 for women)
                72 x serum creatine (mg/dl)

Children aged from 6 to 12 years: 5 mg twice daily (a half tablet twice daily).
Adults and adolescents over 12 years of age: 10 mg once daily (1 tablet).

The tablets need to be swallowed with a glass of liquid.
Elderly subjects: data do not suggest that the dose needs to be reduced in elderly subjects
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 impairement. 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:

 

           [140-age(years)] x weight (kg)
Cl

cr =_____________________________ (x 0.85 for women)
           72 x serum creatinine (mg/dl)

 

Dosing adjustments for adult patients with impaired renal function

Group	CreatineCreatinine Clearance (ml/min)	PosologyDoasge and frequency
Normal	≥80	10 mg once daily
Mild	50 – 79	10 mg once daily
Moderate	30 – 49	5mg 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

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

4.3 Contraindications

History of hypersensitivity to any of the constituents of the formulation or to hydroxyzine. Patients with severe renal impairment at less than 10 ml/min creatinine clearance.

Hypersensitivity to the active substance, to any of the excipients, 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 galactose intolerance, the Lapp lactase deficiency or glucose- galactose malabsorption should not take cetirizine film-coated tablet.

4.4 Special warnings and precautions for use

In patients with significant renal impairment the dosage should be reduced and (refer to 4.2) the product used with caution. Cetirizine should be used with caution in patients with decreased hepatic function. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucosegalactose malabsorption should not take this medicine.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 in epileptic patients and patients at risk of convulsions is recommended.

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.

4.5 Interaction with other medicinal products and other forms of interaction

Concomitant use with alcohol at a blood level of 0.8g/L and with diazepam at therapeutic doses, has been tested and no potentiation was demonstrated. However usual cautions remain advisable in the case of CNS depressants in general due to insufficient experience for the adequate evaluation of the potential risk.

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 Pregnancy and lactation

Animal studies did not reveal a teratogenic effect. There is no evidence of use during pregnancy. The drug is excreted in breast milk. Use of Cetirizine should be avoided during pregnancy or lactation.

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/fetal development, parturition or postnatal development. Caution should be exercised when prescribing to pregnant or breast feeding women because cetirizine passes into breast milk.

 

4.7 Effects on ability to drive and use machines

Clinical studies have demonstrated that Cetirizine is usually non-sedative and should not therefore interfere with activities requiring mental alertness, for example driving or operating machinery. However in sensitive people (less than 10% of patients) who might experience drowsiness, these patients should not drive or operate machinery unless it has been shown not to interfere with their physical and mental capacity. This effect is minimised by administration of half of the recommended dose twice daily.

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 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 adverse effects on the CNS, including somnolence, fatigue, dizziness and headache. In some cases, paradoxical CNS stimulation has been reported.

 

Isolated cases of micturiton difficulty, eye accommodation disorders and dry mouth have been reported. For those patients who are affected the dosage should be halved and taken twice daily.

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 drug.

treatment with cetirizine dihydrochloride.

 

The following adverse drug reactions have also been reported: Abdominal pain, nausea, diarrhoea, pharyngitis and rhinitis.Isolated cases of the following adverse drug reactions have been reported in post-marketingexperience. Data are insufficient to support an estimate of their incidence in the population to be treated.
Blood and lymphatic disorders: thrombocytopenia
Cardiac disorders: tachycardia
Eye disorders: accommodation disorder, blurred vision
Gastro-intestinal disorders: diarrhoea
General disorders and administration site conditions: asthenia, malaise, oedema
Immune system disorders: anaphylactic shock, hypersensitivity
Hepatobiliary disorders: hepatic function abnormal (increased transaminases, alkaline phosphatase,

ã-GT and bilirubin), hepatitis
Investigations: weight increased
Nervous system disorders: convulsions, dysgeusia, paraesthesia, synope
Psychiatric disorders: aggression, agitation, confusion, depression, insomnia
Renal and urinary disorders: micturition difficulity
Skin and subcutaneous tissue disorders: angioneurotic oedema, pruritus, rash, urticaria

 

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 (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 %
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 effects reported during clinical studies and listed above, isolated cases of the following adverse drug reactions have been reported in post-marketing experience. For these less frequently reported undesirable effects, the estimated frequencies (uncommon: ≥1/1,000 to 1/100, rare: ≥1/10,000 to 1/1,000, very rare: 1/10,000) are made based on post-marketing experience.

 

Blood and lymphatic disorders:

Very rare: thrombocytopenia

 

Immune system disorders:

Rare: hypersensitivity

Very rare: anaphylactic shock

 

Psychiatric disorders:

Uncommon: agitation

Rare: aggression, confusion, depression, hallucination, insomnia

Very rare: tic

Nervous system disorders:

Uncommon: paraesthesia

Rare: convulsions, movements disorders

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

Eye disorders:

Very rare: accommodation disorder, blurred vision, oculogyration

 

Cardiac disorders:

Rare: tachycardia

 

Gastro-intestinal disorders:

Uncommon: diarrhoea

 

Hepatobiliary disorders:

Rare: hepatic function abnormal (increased transaminases, alkaline phosphatase, γ-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

 

General disorders and administration site conditions:

Uncommon: asthenia, malaise

Rare: oedema

 

Investigations:

Rare: weight increased

4.9 Overdose

a) Symptoms
Symptoms observed after an important 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 cetrizine

cetirizine.
Should overdose occur, symptomatic or supportive treatment is recommended.
Gastric lavage should be considered following ingestion of a short occurrence. Cetrizine Cetirizine is
not effectively removed by dialysis.

 

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

ATC code: R06AE07
Pharmacotherapeutic group: Antihistamines for systemic use
Cetirizine dihydrochloride 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.

In allergic individuals, cetirizine inhibits the recruitment of eosinophiles after stimulation with
allergens and unselective histamine liberators, by a mechanism that is not primarily explained by the
H1-receptor blocking characteristics of the pharmaceutical.

Pharmacotherapeutic group: Piperazine derivatives, ATC code: R06A E07
Cetirizine, a human metabolite of hydroxyzine, is a potent and selective antagonist of peripheral
H1-receptors. In vitro receptor binding studies have shown no measurable affinity for other than
H1-receptors.

 

In addition to its anti-H

1 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 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 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 the age 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. Cetrizine is eliminated to 60% in unchanged form via the kidneys within 96 hours. At
repeated administration there is no accumulation at hand, nor is the absorption or elimination affected.
At 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.

The steady - state
peak plasma concentrations is approximately 300 ng/ml and is achieved within 1.0 ± 0.5 h. No
accumulation is observed for cetirizine following daily doses of 10 mg for 10 days.
The distribution of pharmacokinetic parameters such as peak plasma concentration (Cmax) and
area under curve (AUC), is unimodal in human volunteers.
The extent of absorption of cetirizine is not reduced with food, although the rate of absorption is
decreased. The extent of bioavailability is similar when cetirizine is given as solutions, capsules
or tablets.

 

The apparent volume of distribution is 0.50 l/kg. Plasma protein binding of cetirizine is 93

± 0.3%. Cetirizine does not modify the protein binding of warfarin.

 

Cetirizine does not undergo extensive first pass metabolism. About two third of the dose are
excreted unchanged in urine. The terminal half-life is approximately 10 hours.
Cetirizine exhibits linear kinetics over the range of 5 to 60 mg.
Special populations

Elderly: Following a single 10 mg oral dose, half-life increased by about 50 % and clearance
decreased by 40 % in 16 elderly subjects compared to the normal subjects. The decrease in
cetirizine clearance in these elderly 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 halflife
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

Non-clinical data reveal no special hazard for humans based on conventional studies of
safety pharmacology, repeated dose toxicity, toxicity to reproduction, genotoxicity or
carcinogenicitygenotoxicity, carcinogenic potential, toxicity to reproduction.

 

6.4 Special precautions for storage

No special precautions for storage.

This medicinal product does not require any special storage conditions.

 

10. DATE OF REVISION OF THE TEXT

May 2009

September 2009

 

Section 2: the following statements we're added 'Excipients: Each tablet contains 74.3mg lactose monohydrate.

For a full list of excipients, see section 6.1.'

Section 3: the following statement was added

'The scoreline is to facilitate breaking for ease of swallowing and not to divide into equal doses.'

 Section 4.4: The standard lactose warning was added.