- Approval Id
- 6e990ac7373747f6
- Drug Approval Emc Name
- Cetirizine Hydrochloride 5mg/5ml Oral Solution
- Drug Name
- Cetirizine Hydrochloride 5mg/5ml Oral Solution
- Company Name
- Cipla EU Ltd
- Company Address
- Dixcart House, Addlestone Road, Bourne Business Park, Addlestone,, KT15 2LE, UK
- Company Website
- http://www.cipla.com
- Company Telephone
- +44 (0)1932 264688
- Company Medical Info Direct Line
- 0800 0472144
- Company Medical Info Email
- Drugsafety@cipla.com
- Company Customer Care Direct Line
- +44 (0)207 399 4883
- Atc Code
- R06AE07
- Legal Category
- Pharmacy
- Authorisation Holder
- Cipla (EU) Limited,
Dixcart House, Addlestone Road
Bourne Business Park
Addlestone Surrey
KT15 2LE
United Kingdom
- Authorisation Number
- PLGB 36390/0349
- Authorisation Date
- 12/12/2024
- Instruction Authorisation Holder
- Cipla (EU) Limited,
Dixcart House, Addlestone Road
Bourne Business Park
Addlestone Surrey
KT15 2LE
United Kingdom
- Instruction Authorisation Number
- PLGB 36390/0349
- Instruction Authorisation Date
- 12/12/2024
- Instruction 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.
- Instruction Dosage Form
- Oral Solution.
Clear, colourless, flavoured solution.
- Instruction 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.
Dosing adjustments for adult patients with impaired renal function
| | | |
| --- | --- | --- |
| Group | Estimated Glomerular Filtration Rate(eGFR) (ml/min) | Dosage and frequency |
| Normal renal function | ≥80 | 10 mg once daily |
| Mildly decreased renal function | 50 – < 90 | 10 mg once daily |
| Moderately decreased renal function | 30 – < 60 | 5 mg once daily |
| Severely decreased renal function | 15 - <30 not requiring dialysis | 5 mg once every 2 days |
| End-stage renal disease | <15 requiring dialysis treatment | 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\* r\*enal 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 end-stage renal disease with an eGFR (estimated Glomerular Filtration Rate) below 15 ml/min.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 passes into breast milk. A risk of side effects in breastfed infants cannot be excluded. 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, myalgia
\*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: https://yellowcard.mhra.gov.uk/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.
- Instruction Pharmacology
- 5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antihistamine 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 and development.
- Instruction 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 months6.4 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.
- Instruction Content
- ## 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.
## Pharmaceutical Form
Oral Solution.
Clear, colourless, flavoured solution.
## 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.
Dosing adjustments for adult patients with impaired renal function
| | | |
| --- | --- | --- |
| Group | Estimated Glomerular Filtration Rate(eGFR) (ml/min) | Dosage and frequency |
| Normal renal function | ≥80 | 10 mg once daily |
| Mildly decreased renal function | 50 – < 90 | 10 mg once daily |
| Moderately decreased renal function | 30 – < 60 | 5 mg once daily |
| Severely decreased renal function | 15 - <30 not requiring dialysis | 5 mg once every 2 days |
| End-stage renal disease | <15 requiring dialysis treatment | 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\* r\*enal 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 end-stage renal disease with an eGFR (estimated Glomerular Filtration Rate) below 15 ml/min.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 passes into breast milk. A risk of side effects in breastfed infants cannot be excluded. 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, myalgia
\*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: https://yellowcard.mhra.gov.uk/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.
## Pharmacological Properties
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antihistamine 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 and development.
## 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 months6.4 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.
