Zyrtec

Cetirizine dihydrochloride.

Each film-coated tablet contains 10 mg of cetirizine dihydrochloride.
Each 1 ml oral solution contains 1 mg of cetirizine dihydrochloride.
Excipients/Inactive Ingredients: Film-coated tablet: Microcrystalline cellulose, Lactose monohydrate, Colloidal anhydrous silica, Magnesium stearate, Opadry Y-1-7000 (contains Hydroxypropylmethylcellulose (E464), Titanium dioxide (E 171), Macrogol 400).
Oral solution: Sorbitol solution at 70% (non-crystallizing), Glycerol (85%), Propylene glycol, Sodium saccharinate, Methyl parahydroxybenzoate, Propyl parahydroxybenzoate, Banana flavor 54.330/A, Sodium acetate, Glacial acetic acid, Purified water.

Pharmacotherapeutic group: Antihistamines for systemic use, piperazine derivatives. ATC Code: R06AE07.
Pharmacology: Pharmacodynamics: 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.
Ex vivo experiments in mice have shown that systemically administered cetirizine does not significantly occupy the cerebral H₁-receptors.
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 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 downregulates 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.
Pharmacokinetics: Film-coated tablet: Cetirizine exhibits linear kinetics over the range 5 to 60 mg. The terminal half-life is approximately 10 hours and the apparent volume of distribution is 0.50 l/kg.
No accumulation is observed for cetirizine following daily doses of 10 mg for 10 days. The steady-state maximum plasma concentration is approximately 300 ng/ml and is achieved within 1.0 ± 0.5 h.
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 distribution of pharmacokinetic parameters as peak level and area under curve, is unimodal in human volunteer and no differences were observed in the kinetics of cetirizine between white and black adult males. 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.
Oral solution: 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 (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.
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.
Film-coated tablet and Oral solution: 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. In infants and toddlers aged 6 to 24 months, it is reduced to 3.1 hours.
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 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.
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 necessary in hepatically impaired patients.
Toxicology: Non-Clinical Information: Oral solution: 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.

Film-coated tablet: In adults and children aged 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 urticaria.
Oral solution: In adults, children aged 2 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 urticaria.

Film-coated tablet: Adults and children over 6 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.
The tablets need to be swallowed with a glass of liquid.
Patients with hepatic impairment and renal impairment: adjustment of the dose is recommended (see 'Patients with moderate to severe renal impairment' as follows).
Patients with hepatic impairment: Adults and children over 6 years old: 5 mg once daily.
Oral Solution:Adults: 10 mg (10 ml of oral solution) once daily.
A 5 mg starting dose (5 ml of oral solution) may be proposed if this leads to satisfactory control of the symptoms.
Children: Children aged from 2 to 6 years: 2.5 mg (2.5 ml of oral solution) twice daily.
Children aged from 6 to 12 years: 5 mg (5 ml of oral solution) twice daily.
Children over 12 years of age: 10 mg (10 ml of oral solution) once daily.
The solution can be swallowed as such.
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 as follows).
Film-coated tablet and Oral solution: Elderly: 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: (See equation.)


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Dosing adjustments for Adult Patients with Impaired renal function: (See Table 1.)


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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.

Symptoms and signs: 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.
Treatment: There is no known specific antidote to cetirizine.
Should overdose occur, symptomatic or supportive treatment is recommended.
Cetirizine is not effectively removed by dialysis

Cetirizine is contraindicated in: history of hypersensitivity to any of the constituents of the formulation, to hydroxyzine or to any piperazine derivatives; patients with severe renal impairment at less than 10 ml/min creatinine clearance.

Alcohol: 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.
Patients at risk of convulsions: Caution in epileptic patients and patients at risk of convulsions is recommended.
Film-coated tablet: Cetirizine dihydrochloride, 10 mg, film-coated tablets: The product contains lactose. Patients with rare hereditary problems of galactose intolerance, (the Lapp lactase deficiency or glucose-galactose malabsorption) should not take this medicine.
Oral solution: Increased risk of urinary retention: Caution should be taken in patients with predisposing factors of urinary retention (e.g. spinal cord lesion, prostatic hyperplasia) as cetirizine may increase the risk of urinary retention.
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: Sorbitol: This product contains sorbitol. Patients with rare hereditary problems of fructose intolerance should not take this medicine.
Parabens: This product contains methyl parahydroxybenzoate or propyl parahydroxybenzoate, which may cause allergic reactions (possibly delayed).
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.
Use in Children: Tablet: The use of the film-coated tablet 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 pediatric formulation of cetirizine.

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.

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 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.
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: (See Table 2.)


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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 reactions at rates of 1 % or greater in children aged from 6 months to 12 years, included in placebo-controlled clinical trials are: (See Table 3.)


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Post Marketing Data: Adverse reactions are ranked under headings of frequency using the following convention: Very common ≥1/10; Common ≥1/100 to <1/10; Uncommon ≥1/1000 to <1/100; Rare ≥1/10000 to <1/1000; Very rare <1/10000; 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.
Psychiatric disorders: Uncommon: agitation.
Rare: aggression, confusion, depression, hallucination, insomnia.
Very rare: tic.
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.
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.
Renal and urinary disorders: Very rare: dysuria, enuresis.
General disorders and administration site conditions: Uncommon: asthenia, malaise.
Rare: oedema.
Investigations: Rare: weight increased.
Oral solution: Metabolism and nutrition disorders: Not known: increased appetite.
Psychiatric disorders: Not known: suicidal ideation.
Ear and labyrinth disorders: Not known: vertigo.
Renal and Urinary disorders: Not known: urinary retention (see Precautions).

Film-coated tablet: Lack of interaction: Pharmacokinetic interaction studies were conducted with cetirizine and pseudoephedrine, antipyrine, cimetidine, ketoconazole, erythromycin, and azithromycin; no pharmacokinetic interactions were observed.
In a multiple dose study of theophylline (400 mg once a day) and cetirizine, there was a small (16%) decrease in clearance of cetirizine, while the disposition of theophylline was not altered by concomitant cetirizine administration.
Studies with cetirizine and cimetidine, glipizide, diazepam, and pseudoephedrine have revealed no evidence of adverse pharmacodynamic interactions.
Studies with cetirizine and azithromycin, erythromycin, ketoconazole, theophylline, antypirine, and pseudoephedrine have revealed no evidence of adverse clinical interactions.
In particular, concomitant administration of cetirizine with macrolides or ketoconazole has never resulted in clinically relevant ECG changes.
Ritonavir: In a multiple dose study of ritonavir (600 mg twice daily) and cetirizine (10 mg daily), the extent of exposure to cetirizine was increased by about 40% while the disposition of ritonavir was slightly altered (-11%) further to concomitant cetirizine administration.
Food: The extent of absorption of cetirizine is not reduced with food, although the rate of absorption is decreased by 1 hour.
Allergy skin tests: Allergy skin tests are inhibited by antihistamines and a wash-out period of 3 days is recommended before performing them.
Oral solution: 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).

Film-coated tablet: Below 25°C.
Oral solution: Store below 30°C.
Shelf-Life: Film-coated tablet: 60 months.
Oral solution: 36 months from the date of manufacturing date.

Antihistamines & Antiallergics

R06AE07 - cetirizine ; Belongs to the class of piperazine derivatives used as systemic antihistamines.

FC tab 10 mg x 1 x 10's. Oral soln 1 mg/mL x 60 mL x 1's.