Cetirizine hydrochloride 10 mg film-coated tablets

Each film-coated tablet contains 10 mg cetirizine hydrochloride.

Excipient: 155.2 mg lactose monohydrate/ film-coated tablet

For a full list of excipients, see section 6.1.

Film-coated tablet.

White to off-white, film-coated, off-rectangular tablets, debossed with 'X' on one side with '20' on the other side. Score line between '2' and '0'.

The tablet can be divided into equal halves.

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.

Oral use.

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

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

The tablets 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: 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 (mg/dl) determination using the following formula:

Dosing adjustments for adult patients with impaired renal function

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.

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).

• Hypersensitivity to the active substance, to any of the excipients, to hydroxyzine or to any piperazine derivatives.

• Patients with severe renal impairment at less than 10 ml/min creatinine clearance.

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 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.

Cetirizine 10 mg film-coated tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose- galactose malabsorption should not take this medicine.

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.

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/fetal development, parturition or postnatal development. Caution should be exercised when prescribing to pregnant women.

Lactation

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.

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

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 hydrochloride.

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:

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 pharmacological trials are:

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 post-marketing experience. For these less frequently reported undesirable effects, the estimated frequencies (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) are made based on post-marketing experience.

Investigations:

Rare: weight increased

Cardiac disorders:

Rare: tachycardia

Blood and lymphatic disorders:

Very rare: thrombocytopenia

Nervous system disorders:

Uncommon: paraesthesia

Rare: convulsions, movement disorders

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

Not known: amnesia, memory impairment

Eye disorders:

Very rare: accommodation disorder, blurred vision, oculogyration

Gastrointestinal disorders:

Uncommon: diarrhoea

Renal and urinary disorders:

Very rare: dysuria, enuresis

Skin and subcutaneous tissue disorders:

Uncommon: pruritus, rash

Rare: urticaria.

Very rare: angioneurotic oedema, fixed drug eruption

General disorders and administration site conditions:

Uncommon: asthenia, malaise

Rare: oedema

Immune system disorders

Rare: hypersensitivity

Very rare: anaphylactic shock

Hepato-billiary disorders:

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

Psychiatric disorders:

Uncommon: agitation

Rare: aggression, confusion, depression, hallucination, insomnia

Very rare: tics

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.

Pharmacotherapeutic group: Piperazine derivatives, ATC code: R06AE07

Cetirizine, a human metabolite of hydroxyzine, is a potent and selective antagonist of peripheral H₁-receptors. In vitro receptors 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.

The steady-state peak plasma concentrations is approximately 300 ng/ml and is achieved within 1.0 ± 0.5 h. No accumulation is observed for cetirizine following daily doses of 10 mg for 10 days. The distribution of pharmacokinetic parameters such as peak plasma concentration (C_max) 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 a 70% decrease in clearance compared to healthy volunteers.

Patients on haemodialysis (creatinine clearance less than 7 ml/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 normals. 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 disease (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.

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential or toxicity to reproduction.

Tablet core:

Lactose monohydrate

Crospovidone

Starch, pregelatinised (maize)

Magnesium stearate

Film-coat:

Hypromellose

Titanium dioxide

Macrogol 400

Not applicable.

Blister pack: 1 year

HDPE bottle pack: 18 months

Store below 25°C.

PVC-PVDC Aluminium blisters: 1,2, 7, 10, 14, 15, 20, 21, 30, 50, 60, 90, 98 and 100 film-coated tablets.

HDPE bottle: 250 film-coated tablets.

Not all pack sizes may be marketed.

No special requirements.

Aurobindo Pharma (Malta) Limited

46/2, South street, Valletta, VLT 11, Malta

PL 32256/0036

03/07/2009

17/06/2011