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SUMMARY OF PRODUCT CHARACTERISTICS
1. NAME OF THE MEDICINAL PRODUCT
Zyrtec 10 mg, film-coated tablets
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Cetirizine dihydrochloride, 10 mg, film-coated tablets Each film-coated tablet contains 10 mg of cetirizine dihydrochloride.
Excipients
Cetirizine dihydrochloride, 10 mg, film-coated tablets Microcrystalline cellulose 37,0 mg, Lactose 66,4 mg, Colloidal anhydrous silica 0,6 mg, Magnesium stearate 1-1,5 mg, Opadry Y-1-7000 3,45 mg, Hydroxypropylmethylcellulose (E464) 2,156 mg, Titanium dioxide (E 171) 1,078 mg, Macrogol 400 0,216 mg.
3. PHARMACEUTICAL FORM
White, oblong, film-coated tablet, with breakline and Y-Y logo.
4. CLINICAL INFORMATION
4.1 Indications
For the relief of:
- nasal and ocular symptoms of seasonal and perennial allergic rhinitis.
- symptoms of urticaria.
4.2 Dosage and Administration
The tablets need to be swallowed with a glass of liquid. For oral use.
Adults
10 mg (1 tablet) once daily. A 5 mg starting dose (half of the tablet) may be proposed if this leads to satisfactory control of the symptoms.
Children
Children aged from 6 to 12 years 5 mg (half of the tablet) twice daily.
Children over 12 years of age 10 mg (1 tablet) once daily.
Elderly
Data does not suggest that the dose needs to be reduced in elderly subjects provided that the renal function is normal.
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 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
[ ] ( x forwomen )
xserumcreatinine mg dl
age years xweight kg 0. 85 72 ( / )
CLcr =
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.
Please be aware that in some markets, film-coated tablet may not be indicated in children below 12 years.
Allergy skin tests Allergy skin tests are inhibited by antihistamines and a wash-out period of 3 days is recommended before performing them.
Food The extent of absorption of cetirizine is not reduced with food, although the rate of absorption is decreased.
Excipients LactoseCetirizine dihydrochloride, 10 mg, film-coated tablets These products contain lactose. Patients with rare hereditary problems of galactose intolerance, (the Lapp lactase deficiency or glucose-galactose malabsorption) should not take this medicine.
4.5 Interactions
Due to the pharmacokinetic, pharmacodynamic and tolerance profile of cetirizine, no interactions are expected with this antihistamine. Neither pharmacodynamic nor significant pharmacokinetic interaction was reported in drug-drug interactions studies performed, notably with pseudoephedrine or theophylline (400 mg/day).
4.6 Pregnancy and Lactation
Fertility
There are no relevant data available.
Pregnancy
Caution should be exercised when prescribing to pregnant women.
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.
Lactation
Caution should be exercised when prescribing cetirizine to lactating women. Cetirizine is excreted in human milk at concentrations representing 25% to 90% of those measured in plasma, depending on sampling time after administration.
4.7 Ability to perform tasks that require judgement, motor or cognitive skills
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 sensitive patients, concurrent use with alcohol or other CNS depressants may cause additional reductions in alertness and impairment of performance.
4.8 Adverse Reactions
Clinical Trial Data
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 H 1 -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. Double blind controlled clinical trials comparing cetirizine to placebo or other antihistamines at the recommended dosage (10 mg daily for cetirizine), of which
Adverse 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 Data
Adverse reactions are ranked under headings of frequency using the following convention: Very common ≥1/ Common ≥1/100 to <1/ Uncommon ≥1/1000 to <1/ Rare ≥1/10000 to <1/ Very rare <1/ Not known (cannot be estimated from the available data).
Blood and lymphatic system 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 : tic Not known: suicidal ideation
Nervous system disorders Uncommon: paraesthesia Rare: convulsions 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: hepatic function abnormal (transaminases increased, blood bilirubin increased, blood alkaline phosphatase increased, Gamma-glutamyl transferase increased)
Skin and subcutaneous tissue disorders Uncommon : pruritus, rash Rare: urticaria Very rare : angioedema, drug eruption
Mechanism of Action and Pharmacodynamic effects
Cetirizine, a human metabolite of hydroxyzine, is a potent and selective antagonist of peripheral H 1 -receptors. In vitro receptor binding studies have shown no measurable affinity for receptors other than H 1 -receptors. Ex vivo experiments in mice have shown that systemically administered cetirizine does not significantly occupy the cerebral H 1 -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 inflammatory cells, notably eosinophils, in the skin and conjunctiva of atopic subjects submitted to antigen challenge, and the dose of 30 mg/day inhibits the influx of eosinophils in the bronchoalveolar lavage fluid during a late-phase bronchial constriction induced by allergen inhalation in asthmatic subjects. Moreover, cetirizine inhibits the late-phase inflammatory reaction induced in chronic urticaria patients by intradermal administration of kallikrein. It also down-regulates the expression of adhesion molecules, such as ICAM-1 and VCAM-1, which are markers of allergic inflammation. 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. The onset of activity after a single 10 mg dose occurs within 20 minutes in 50 % of the subjects and within one hour in 95 %. This activity persists for at least 24 hours after a single administration. 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 Pharmacokinetics
Absorption
No accumulation is observed for cetirizine following daily doses of 10 mg for 10 days. The steady - state peak plasma concentration 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 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.
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.
Metabolism and Elimination
Cetirizine does not undergo extensive first pass metabolism. About two-thirds of the dose is excreted unchanged in urine. The terminal half-life is approximately 10 hours.
Cetirizine exhibits linear kinetics over the range 5 to 60 mg.
Special patient populations
Children The half-life of cetirizine was about 6 hours in children of 6-12 years and 5 hours in children 2-6 years.
Elderly Following a single 10 mg oral dose, the 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.
Renal impairment The pharmacokinetics of the drug was similar in patients with mild impairment (creatinine clearance higher than 40 ml/min) and normal volunteers. Moderately renally impaired patients had a 3-fold increase in half-life and 70% decrease in clearance compared to normal volunteers. Patients on haemodialysis (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.
6.6 Use and Handling
There are no special requirements for use or handling of this product. Not all presentations are available in every country.
7. MARKETING AUTHORISATION HOLDER
GlaxoSmithKline Export Limited, 980 Great West Road, Brentford, Middlesex, TW 9GS, UK
8. MANUFACTURER
Bulk manufacturer - UCB Farchim S.A., Z.I. de Planchy, Chemin de Croix Blanche 10, CH-1630 Bulle, Switzerland
Packager, batch releaser - Aesica Pharmaceuticals S.r.I., Via Pragila, 15- Pianezza (TO), Italy
