SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Benadryl Allergy Liquid Release 10 mg Capsules

2    QUALITATIVE AND QUANTITATIVE    COMPOSITION

Each soft capsule contains 10 mg cetirizine dihydrochloride.

For the full list of excipients, see section 6.1. The product contains a maximum of 19.3 mg sorbitol per capsule dose.

3    PHARMACEUTICAL FORM

Capsule, soft.

Each capsule has a colourless to slightly yellow, clear shell containing a clear, colourless viscous fill. Each soft gel capsule has the logo "C10" printed with black ink.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Benadryl Allergy Liquid Release 10mg Capsules is indicated in children aged 12 years and above, adolescents and adults:

o for the relief of nasal and ocular symptoms of seasonal and perennial allergic rhinitis.

o for the relief of symptoms of chronic idiopathic urticaria.

4.2    Posology and method of administration

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

= [14°-ggejyears)\xweight⁽kg> (_fmwome„)

^CLcr    72 x serum creatinine (mg / dl)

Dosing adjustments for adult patients with impaired renal function

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

*The product cannot be halved to give the required dose adjustment in renally-impaired patients.

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, and his body weight.

Patients with hepatic impairment: no dose adjustment is needed in patients with solely hepatic impairment.

Patients with hepatic impairment and renal impairment: adjustment of the dose is recommended (see Patients with renal impairment above).

4.3 Contraindications

History of hypersensitivity to the active substance, soya, peanut, or to any of the excipients listed in section 6.1, or to hydroxyzine or to any piperazine derivatives.

Patients with moderate to severe renal impairment at less than 50ml/min creatinine clearance (as the product cannot be halved to give the required dose adjustment).

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 0.5g/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.

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

This product contains sorbitol (E420). Patients with rare hereditary problems of fructose intolerance should not take this medicine.

Paediatric Population

The use of the capsule formulation is not recommended in children aged less than 12 years since this formulation does not allow for appropriate dose adaptation.

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 (400mg/day).

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

4.6 Fertility, pregnancy and lactation

Pregnancy

For cetirizine very rare clinical data on exposed pregnancies are available. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal 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% those measured in plasma, depending on sampling time after administration. Therefore, caution should be exercised when prescribing cetirizine to lactating women.

4.7 Effects on ability to drive and use machines

Objective measurements of driving ability, sleep latency and assembly line performance have not demonstrated any clinically relevant effects at the recommended dose of 10mg.

Patients intending to drive, engaging in potentially hazardous activities or operating machinery should not exceed the recommended dose and should take their response to the medicinal product into account. In sensitive patients, concurrent use with alcohol or other CNS depressants may cause additional reductions in alertness and impairment of performance.

4.8 Undesirable effects

Clinical studies have shown that cetirizine at the recommended dosage has minor adverse effects on the CNS, including somnolence, fatigue, dizziness and headache. In some cases, paradoxical CNS stimulation has been reported.

Although cetirizine is a selective antagonist of peripheral H1-receptors and is relatively free of anticholinergic activity, isolated cases of micturition difficulty, eye accommodation disorders and dry mouth have been reported.

Instances of abnormal hepatic function with elevated hepatic enzymes accompanied by elevated bilirubin have been reported. Mostly this resolves upon discontinuation of the drug.

Clinical trials

Double blind controlled clinical or pharmacoclinical trials comparing cetirizine to placebo or other antihistamines at the recommended dosage (10mg 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 10mg in the placebo-controlled trials at rates of 1.0% or greater:

Adverse event	Cetirizine 10mg	Placebo
(WHO-ART)	(n= 3260)	(n = 3061)
Body as a whole - general disorders Fatigue	1.63%	0.95%
Central and peripheral nervous system disorders	1.10%	0.98%
Dizziness Headache	7.42%	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 (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 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 the 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 (>U10,000 to <1/1,000); very rare (<1/10,000), not known (cannot be estimated from the available data)

Blood and lymphatic disorders :

Very rare: thrombocytopenia

Immune system disorders:

Rare: hypersensitivity Very rare: anaphylactic shock

Metabolism and nutrition disorders:

Not known: increased appetite

Psychiatric disorders:

Uncommon: agitation

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

Not known: suicidal ideation

Nervous system disorders:

Uncommon: paraesthesia Rare: convulsions

Very rare: dysgeusia, dystonia, dyskinesia, 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

Gastro-intestinal disorders:

Uncommon: diarrhoea

Hepatobiliary disorders:

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

Skin and subcutaneous tissue disorders:

Uncommon: pruritus, rash Rare: urticaria

Very rare: angioneurotic oedema, fixed drug eruption

Renal and urinary disorders:

Very rare: dysuria, enuresis Not known: urinary retention

General disorders and administration site conditions :

Uncommon: asthenia, malaise Rare: oedema

Investigations:

Rare: weight increased

Reporting of suspected adverse reactions

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

4.9 Overdose

Symptoms

Symptoms observed after an overdose of cetirizine are mainly associated with CNS effects or with effects that could suggest an anticholinergic effect.

Adverse events reported after an intake of at least 5 times the recommended daily dose are: confusion, diarrhoea, dizziness, fatigue, headache, malaise, mydriasis, pruritus, restlessness, sedation, somnolence, stupor, tachycardia, tremor, and urinary retention.

Management

There is no known specific antidote to cetirizine.

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

Cetirizine is not effectively removed by dialysis.

5    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

Pharmacotherapeutic group: 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-H1 effect, cetirizine was shown to display anti-allergic activities: at a dose of 10mg 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 10mg 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 10mg 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 60mg 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

The steady-state peak plasma concentrations is approximately 300ng/ml and is achieved within 1.0 ± 0.5 h. No accumulation is observed for cetirizine following daily doses of 10mg 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 60mg.

Special populations

Elderly: Following a single 10mg 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 40ml/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 haemodialysis (creatinine clearance less than 7ml/min) given a single oral 10mg 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 20mg 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

Capsule contents Macrogol 600

Potassium Hydroxide 43% w/w Povidone K30 Purified water

Capsule shell

Gelatin

Sorbitol (E420)

Glycerol Purified Water Lecithin

Medium chain triglycerides Black ink

Components of black printing ink

Propylene Glycol Black iron oxide (E172)

Polyvinyl Acetate Phthalate Macrogol 400 Ammonium Hydroxide

6.2    Incompatibilities

Not applicable.

6.3    Shelf life

36 months

6.4    Special precautions for storage

Store below 30°C.

6.5    Nature and contents of container

PVC/PE/PVdC blisters of 7 capsules sealed with aluminium lidding foil, packed into cardboard cartons.

6.6    Special precautions for disposal

No special requirements

7    MARKETING AUTHORISATION HOLDER

McNeil Products Limited Foundation Park Roxborough Way Maidenhead Berkshire United Kingdom SL6 3UG

8    MARKETING AUTHORISATION NUMBER(S)

PL 15513/0378

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

20/04/2011

10    DATE OF REVISION OF THE TEXT

01/12/2014