Document: spc-doc_PL 20395-0129 change

• spc-doc_PL 00142-0606
• spc-doc_PL 13931-0099
• spc-doc_PL 14776-0069
• spc-doc_PL 17907-0047
• spc-doc_PL 20395-0129

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SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Cetirizine Hydrochloride 10mg film-coated Tablets Bell’s Healthcare Allergy Relief 10mg film-coated Tablets

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

One film-coated tablet contains cetirizine hydrochloride 10 mg.

For a full list of excipients, see section 6.1

3    PHARMACEUTICAL FORM

Film-coated tablet.

White coloured, circular, biconvex film coated tablet. Marked with ‘A’ on one side and a break-line on the other

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Adults and adolescents over 12 years of age:

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

Children 6-12 years:

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

4.2    Posology and method of administration

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

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

Children aged from 6 to 12 years: 5mg twice daily (a half tablet twice daily).

For children weighing less than 30 kg:

/ tablet (5mg) taken once daily.

Clinical trials in children have not exceeded four weeks.

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

Cetirizine is contraindicated in patients with severe renal impairment.

Patients with moderate to severe renal impairment: the dosing intervals must be individualized according to renal function. Refer to the following table and adjust the dose as indicated. To use this dosing table, an estimate of the patient’s creatinine clearance (CLcr) in ml/min is needed. The CLcr (ml/min) may be estimated from serum creatinine (mg/dl) determination using the following formula:

Dosing adjustments for adult patients with impaired renal function

Group	Creatinine clearance (ml/min)	Dosage and frequency
Normal	>80	10 mg once daily
Mild	50 - 79	10 mg once daily
Moderate	30 - 49	5 mg once daily
Severe	<30	5 mg once every 2 days
End-stage renal disease -Patients undergoing dialysis	<10	Contra-indicated

In pediatric patients suffering from renal impairment, the dose will have to be adjusted on an individual basis taking into account the renal clearance of the patient, 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

Cetirizine hydrochloride 10 mg Film Coated Tablets are contraindicated in

-    patients with a history of hypersensitivity to any of the constituents of the formulation, to hydroxyine or to any piperazine derivatives.

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

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose- galactose malabsorption should not take Cetirizine Film-Coated Tablets.

4.4 Special warnings and precautions for use

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

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

At therapeutic doses, no clinically significant interactions have been demonstrated with alcohol (for a blood alcohol level of 0.5 g/L). Nevertheless, precaution is recommended if alcohol is taken concomitantly.

Caution is recommended with concomitant use of CNS depressants.

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.

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

4.5 Interaction with other medicinal products and other forms of interaction

Due to the pharmacokinetic, pharmacodynamic and tolerance profile of cetirizine, no interactions are expected with this antihistamine. Actually, neither pharmacodynamic nor significant pharmacokinetic interaction was reported in drug-drug interactions studies performed, notably with pseudoephedrine or theophylline (400 mg/day).

The extent of absorption of cetirizine is not reduced with food, although the rate of absorption is decreased.

Caution is recommended with the concomitant use of CNS depressants

4.6 Fertility, Pregnancy and lactation

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

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

Lactation

No data concerning the excretion of cetirizine into human milk are available. Cetirizine is excreted in human milk at concentrations representing 0.25 to 0.90 those measured in plasma, depending on sampling time after administration. Therefore, caution should be exercised when prescribing cetirizine to lactating women

4.7 Effects on ability to drive and use machines

Studies in healthy volunteers at 20 and 25mg/day have not revealed adverse effects on alertness or reaction time. However, patients are advised not to exceed the recommended dose if driving or operating machinery even though cetirizine has no or negligible influence on these parameters.

In sensitive patients, concurrent use with alcohol or other CNS depressants may cause additional reductions in alertness and impairment of performance.

4.8 Undesirable effects

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

Double blind controlled clinical or pharmacoclinical trials comparing cetirizine to placebo or other antihistamines at the recommended dosage (10 mg daily for cetirizine), of which quantified safety data are available, included more than 3200 subjects exposed to cetirizine.

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

Adverse event	Cetirizine	Placebo
(WHO-ART)	10 mg	(n =
	(n= 3260)	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	0.98 %	1.08 %
Dry mouth	2.09 %	0.82 %
Nausea	1.07 %	1.14 %
Psychiatric disorders
Somnolence	9.63 %	5.00 %
Respiratory system disorders Pharyngitis	1.29 %	1.34 %

Although statistically more common than under placebo, somnolence was mild to moderate in the majority of cases. Objective tests as demonstrated by other studies have demonstrated that usual daily activities are unaffected at the recommended daily dose in healthy young volunteers.

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

Adverse drug reactions	Cetirizine	Placebo
(WHO-ART)	(n=1656)	(n =1294)
Gastro-intestinal system disorders Diarrhoea	1.0 %	0.6 %
Psychiatric disorders
Somnolence	1.8 %	1. 4 %
Respiratory system disorders
Rhinitis	1.4 %	1.1 %
Body as a whole - general disorders Fatigue	1.0 %	0.3 %

Post-marketing experience

In addition to the adverse effects reported during clinical studies and listed above, isolated cases of the following adverse drug reactions have been reported in postmarketing experience.

Undesirable effects are described according to MedDRA System Organ Class and by estimated frequency based on post-marketing experience.

Frequency estimates: 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 system disorders:

Very rare: thrombocytopenia

Immune system disorders:

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

Very rare: anaphylactic shock

Psychiatric disorders:

Uncommon: agitation

Rare: aggression, confusion, depression, hallucination, insomnia Very rare: tics

Not known: suicidal ideation

Nervous system:

Uncommon: paraesthesia.

Rare: convulsions, movement disorders

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

Not known: amnesia, memory impairment

Eye disorders:

Very rare: accommodation disorder, blurred vision, oculogyration

Ear and labyrinth disorders:

Not known: vertigo

Cardiac disorders:

Rare: tachycardia

Gastrointestinal disorders:

Uncommon: diarrhoea

Hepatobiliary disorders:

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

Skin and subcutaneous tissue disorders:

Uncommon: skin rash, pruritus Rare: urticaria

Very rare: angioedema, erythema multiforme, fixed drug eruption

Renal and urinary disorders:

Very rare: dysuria, enuresis, micturition difficulties

Not known: urinary retention (see section warnings and precautions)

General disorders and administration site conditions:

Uncommon: asthenia, malaise Rare: oedema

Investigations:

Rare: weight increased

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

4.9 Overdose

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

Symptoms

Symptoms observed after an overdose of cetirizine are mainly associated with CNS effects or with effects that could suggest an anticholinergic effect. Adverse events reported after 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. The patient should be kept under clinical observation for at least four hours after ingestion, and the blood pressure, heart rate and vital signs monitored until stable. In symptomatic cases, ECG should be performed.

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

There is no specific antidote.

Cetirizine is not effectively removed by dialysis.

5.1 Pharmacodynamic properties

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 receptors other than H₁-receptors.

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 conjuctivia 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 glare reactions induced by very high concentrations of histamine into the skin, but the correlation with efficacy is not established.

In a 35-day study in children aged 5 to 12, no tolerance to the antihistamine effect (suppression of wheal and flare) of cetirizine was found. When a treatment with cetirizine is stopped after repeated administration, the skin recovers its normal reactivity to histamine within 3 days.

In a six-week, placebo-controlled study of 186 patients with allergic rhinitis and concomitant mild to moderate asthma, cetirizine 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 give 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

Peak blood levels in the order of 0.3pg/ml are reached within about one hour after the oral administration of cetirizine. The terminal half-life is approximately ten hours in adults and six hours in children aged 6 - 12 years. This is consistent with the urinary excretion half-life of the drug. The cumulative urinary excretion represents about two thirds of the dose given for both adults and children.

Consequently, the apparent plasma clearance in children is higher than that measured in adults. Plasma levels are linearly related to the dose given. A high proportion of cetirizine is bound to human plasma proteins.

5.3 Preclinical safety data

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

Preclinical results were observed only at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Tablet core

Lactose monohydrate

Microcrystalline cellulose

Colloidal anhydrous silica

Maize starch

Talc

Magnesium stearate Coating

Titanium dioxide (E171)

Hypromellose Lactose monohydrate Macrogol Sodium citrate

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years.

6.4 Special precautions for storage

No special precautions for storage.

6.5 Nature and contents of container