This information is intended for use by health professionals

1. Name of the medicinal product

Cetirizine Hydrochloride 5mg/5ml Oral Solution

2. Qualitative and quantitative composition

Each ml of solution contains 1 mg cetirizine hydrochloride

Excipients with known effect:

- one mL of solution contains 500 mg sorbitol (solution at 70 %, non crystallizing)

- one mL of solution contains 2 mg methyl parahydroxybenzoate (E218)

- one mL of solution contains 0.20 mg propyl parahydroxybenzoate (E216)

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Oral Solution.

Clear, colourless, flavoured solution.

4. Clinical particulars
4.1 Therapeutic indications

In adults and paediatric patients 2 years 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

Posology

Children aged from 2 to 6 years

2.5 mg twice daily (2.5 mL oral solution twice daily).

Children aged from 6 to 12 years

5 mg twice daily (5 mL oral solution twice daily).

Adults and adolescents over 12 years of age

10 mg once daily (10 mL oral solution).

Elderly

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 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 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 (mL/min) clearance

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

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.

Hepatic impairment

No dose adjustment is needed in patients with solely hepatic impairment.

Hepatic impairment and renal impairment

Dose adjustment is recommended (see Patients with moderate to severe renal impairment above).

Method of administration:

The solution can be swallowed as such.

4.3 Contraindications

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

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

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.

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

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

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

Sorbitol

The additive effect of concomitantly administered products containing sorbitol (or fructose) and dietary intake of sorbitol (or fructose) should be taken into account.

The content of sorbitol in medicinal products for oral use may affect the bioavailability of other medicinal products for oral use administered concomitantly.

Methyl and propyl parahydroxybenzoate

Methyl parahydroxybenzoate (E218) and propyl parahydroxybenzoate (E216) may cause allergic reactions (possibly delayed).

Sodium

This medicine contains less than 1 mmol sodium (23 mg) per mL, that is to say essentially 'sodium-free'.

The elimination of cetirizine may be impaired in patients with impaired hepatic and renal function. Caution should be exercised when administering cetirizine to these patients (see section 4.2 Posology, section 4.3 Contraindications)

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.

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.

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 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. They should not exceed the recommended dose and should take their response to the medicinal product into account.

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.

Listing of ADRs

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)

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 %

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 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

(WHO-ART)

Cetirizine

(n=1656)

Placebo

(n =1294)

Gastro-intestinal disorders

Diarrhoea

 

1.0 %

 

0.6 %

Psychiatric disorders

Somnolence

 

1.8 %

 

1. 4 %

Respiratory, thoracic and mediastinal disorders

Rhinitis

 

1.4 %

 

1.1 %

General disorders and administration site conditions

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

Not known: hepatitis

Skin and subcutaneous tissue disorders

Uncommon: rash, pruritus

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

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 the Yellow Card Scheme website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

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

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

There is no known specific antidote to cetirizine.

Cetirizine is not effectively removed by haemodialysis.

5. Pharmacological properties
5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antihistamines for systemic use, piperazine derivatives

ATC Code: R06A E07

Mechanism of action

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

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.

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 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 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.

Paediatric population

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.

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.

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 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

About two third of the dose are excreted unchanged in urine. The terminal half-life is approximately 10 hours, and no accumulation is observed for cetirizine following daily doses of 10 mg for 10 days.

Linearity/non-linearity

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.

Paediatric 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.

Renal impairment

The pharmacokinetics of the drug was 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).

Hepatic impairment

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

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

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:

200 ml bottle.

Packaging:

Type III amber glass bottle with Tamper proof polypropylene closure and Polyethylene Terepthalate (PET) amber bottle with Tamper proof polypropylene closure.

6.6 Special precautions for disposal and other handling

No special requirements for disposal.

7. Marketing authorisation holder

Cipla (EU) Limited,

Dixcart House, Addlestone Road

Bourne Business Park

Addlestone Surrey

KT15 2LE

United Kingdom

8. Marketing authorisation number(s)

PL 36390/0023

9. Date of first authorisation/renewal of the authorisation

03/11/2011

10. Date of revision of the text

15/11/2018