Cetirizine Dihydrochloride 10mg Film-Coated Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Cetirizine Dihydrochloride 10mg Film-coated Tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each film-coated tablet contains 10 mg of Cetirizine Dihydrochloride Excipients with known effects:
Each film-coated tablet contains 100.2 mg of lactose monohydrate.
For a full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Film-coated tablet. The diameter of each tablet is 8mm.
White coloured, circular, biconvex film coated tablets, marked with ‘A’ on one side and a breakline score on the other.
The tablet can be divided into equal halves.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
In adults and children 6 year 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
Adults and adolescents over 12 years of age:
10 mg once daily (1 tablet). A 5 mg starting dose (1 half tablet) may be proposed if this leads to satisfactory control of the symptoms.
Older people:
At present there is no data to 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 excreted 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:
CUx=
[l40 - age(years) ] x weight (kg) 72 x serum crvaiinifte (mg l dl)
■a: 0.8 5 for women'
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 |
<10 |
Contra-indicated |
|
disease - Patients | ||
|
undergoing dialysis |
Paediatric population
The tablet formulation should not be used in children under 6 years of age as it does not allow the necessary dose adjustments.
Children aged 6 to 12 years: 5 mg twice daily (a half tablet twice daily).
Adolescents above 12 years: 10 mg once daily (1 tablet). A 5 mg starting dose (a half tablet) may be proposed if this leads to satisfactory control of the symptoms.
In pediatric patients suffering from renal impairment, the dose will have to be adjusted on an individual basis taking into account the renal clearance, age and body weight of the patient.
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).
Method of administration
The tablets need to be swallowed with a glass of liquid.
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.
Allergy skin tests are inhibited by antihistamines and a wash-out period (of 3 days) is required before performing them.
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose- galactose malabsorption should not take cetirizine film-coated tablet.
Paediatric population
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.
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 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).
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
Prospectively collected data in more than 700 cases of pregnancy outcomes indicate no malformative nor feto/neonatal toxicity of cetirizine with clear causal relationship. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/fetal development, parturition or postnatal development. Caution should nevertheless 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 Hi-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 adverse drug reactions (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 |
1.63 % |
0.95 % |
|
conditions | |||
|
Fatigue | |||
|
Nervous system disorders | |||
|
Dizziness |
1.10 % |
0.98 % | |
|
Headache |
7.42 % |
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 |
1.29 % |
1.34 % |
|
Pharyngitis |
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 (>1A0,000 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: tic
Not known: suicidal ideation
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, 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 website: 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 may be considered shortly after ingestion of the drug.
Cetirizine is not effectively removed by haemodialysis.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Piperazine derivatives, ATC code: R06A E07 Mechanism of action
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.
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 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 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 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 Older people :
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 younger 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 were 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 patients with hepatic impairment 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.
6.1 List of excipients
Tablet core:
Microcrystalline cellulose (Avicel PH 102) Lactose monohydrate for DC (Tabletose 80) Colloidal anhydrous silica (Aerosil)
Maize starch Purified talc Magnesium stearate
Film Coating:
Opadry white 31F58914 containing:
- Hypromellose 15cP
- Lactose monohydrate
- Titanium dioxide
- Macrogol
- Sodium citrate
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years
6.4 Special precautions for storage
This medicinal product does not require any special temperature storage conditions. Keep the blister in the outer carton in order to protect from light.
6.5
Nature and contents of container
Aluminium/PVC clear blister strips, containing 7, 14, 21, 28, 30 or 60 tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
7 MARKETING AUTHORISATION HOLDER
Cipla (EU) Limited,
Hillbrow House,
Hillbrow Road,
Esher,
Surrey,
KT10 9NW
8 MARKETING AUTHORISATION NUMBER(S)
PL 36390/0126
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
09/06/2011
10 DATE OF REVISION OF THE TEXT
08/10/2015