Cetimax

Document: Cetimax film-coated tablet ENG SmPC change

SUMMARY OF PRODUCT CHARACTERISTICS

1. NAME OF THE MEDICINAL PRODUCT

Cetimax 10 mg film-coated tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 10 mg cetirizine dihydrochloride.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL form

Film-coated tablet.

A white, round, convex one-side scored tablet with logo “5”. Diameter is 7 mm.

The tablet can be divided into equal doses.

4. Clinical particulars

4.1 Therapeutic indications

In adults and paediatric patients 6 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

Adults

10 mg once daily (1 tablet).

Older people

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 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 (CL_cr) in ml/min is needed. The CL_cr (ml/min) may be estimated from serum creatinine determination (mg/dl) using the following formula:

CL_cr =

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 - ≤10 Contra-indicated

Patients undergoing dialysis

Patients with hepatic impairment

No dose adjustment is needed in patients with solely hepatic impairment. In patients with hepatic impairment and renal impairment, adjustment of the dose is recommended (see Patients with moderate to severe renal impairment above).

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

Adolescents above 12 years: 10 mg once daily (1 tablet).

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.

Method of administration

The tablets need to be swallowed with a glass of liquid.

4.3 Contraindications

Hypersensitivity to the active substance to any of the excipients listed in section 6.1, to hydroxyzine, or to any piperazine derivatives.

Patients with severe renal impairment with a creatinine clearance below 10 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.

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

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.It is recommended to use a

paediatric formulation of cetirizine.

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 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.

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 reaction

(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 in 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 adverse drug reactions 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.

The frequency classification of adverse reactions is following:

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 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: tics

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: hepatic function abnormal (increased transaminases, alkaline phosphatase, γ-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 national reporting system listed in Appendix V

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 and supportive treatment is recommended. Gastric lavage should be considered if the ingestion of cetirizine is recent.

Cetirizine is not effectively removed by dialysis.

5. 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 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, it has been demonstrated that cetirizine 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 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 (C_max) 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 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

The terminal half-life is approximately 10 hours and no accumulation is observed for cetirizine following

daily doses of 10 mg for 10 days.

About two third of the dose are excreted unchanged in urine

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 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 normal subjects. Cetirizine was poorly eliminated 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.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Tablet core:

- Microcrystalline cellulose

- Pregelatinised starch

- Croscarmellose sodium

- Silica, colloidal anhydrous

- Magnesium stearate

Tablet coating:

- Polydextrose

- Hypromellose

- Titanium dioxide (E 171)

- Macrogol

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years.

6.4 Special precautions for storage

Store below 25 C.

Nature and contents of container

PVC/PVdC/Aluminium blister with carton.

Pack sizes: 7, 10, 14, 20, 30, 50 and 100 tablets.

Not all pack sizes may be marketed.

Special precautions for disposal and other handling

No special requirements.

7. MARKETING AUTHORISATION HOLDER

Vitabalans Oy

Varastokatu 8

FI-13500 Hämeenlinna

FINLAND

Tel: +358 (3) 615600

Fax: +358 (3) 6183130

8. MARKETING AUTHORISATION NUMBER(S)

<[To be completed nationally]>

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

29 Sep, 2010

10. DATE OF REVISION OF THE TEXT

15^thJanuary 2016