AHFS Class:

• Second Generation Antihistamines 4:08

Generic Name(s):

• Cetirizine Hydrochloride

Associated Monographs

• Antihistamines General Statement

Cetirizine, a piperazine-derivative, has been classified as a second generation antihistamine.1,2,3,12

Cetirizine shares the uses of other antihistamines, including the management of seasonal or perennial allergic rhinitis and chronic idiopathic urticaria.1,2,3,20,25,26,27,28,29,46,49,68,69,70,71,72 For additional information on these and other uses of antihistamines, see Uses in the Antihistamines General Statement 4:00.

Allergic Rhinitis

Cetirizine alone or in fixed combination with pseudoephedrine hydrochloride is used for self-medication 68,69,70,71 to provide symptomatic relief of seasonal allergic rhinitis (e.g., hay fever) or other upper respiratory allergies.1,2,3,12,20,25,26,27,42,46,49,62,63 Cetirizine alone or in fixed combination with pseudoephedrine hydrochloride also is used for the symptomatic treatment of perennial allergic rhinitis.1,2,3,20,63 It is recommended that the fixed combination generally be used only when both the antihistamine and nasal decongestant activity of the combination preparation are needed concurrently.63

Antihistamines, including cetirizine, are used in the management of seasonal allergic rhinitis.1,2,3,20,25,26,27,42,49,62 Antihistamines are not curative and merely provide palliative relief; since seasonal allergic rhinitis may be a chronic, recurrent condition, successful therapy often may require long-term intermittent use of these drugs.7,8,9,10 In the treatment of seasonal allergic rhinitis, antihistamines are more likely to be beneficial when therapy is initiated at the beginning of the hay fever season when pollen counts are low.8,10,50,52 Antihistamines are less likely to be effective when pollen counts are high, when pollen exposure is prolonged, and when nasal congestion is prominent.10,51 Chronic nasal congestion and headache caused by edema of the paranasal sinus mucosa often are refractory to antihistamine therapy.8,9,10,53 Antihistamines generally are not effective in relieving symptoms of nasal obstruction.8,9,54

Following oral administration of a 10-mg dose of cetirizine hydrochloride in patients with seasonal allergic rhinitis who were exposed to allergens (e.g., pollen, mold), symptomatic relief of allergic reactions was evident within 2 hours and was maintained for about 24 hours.27,62 In short-term (1-6 weeks) controlled clinical trials in patients 12 years of age and older, cetirizine hydrochloride (5-20 mg daily) was more effective than placebo and at least as effective as astemizole (no longer commercially available in the US) (10 mg daily), chlorpheniramine, diphenhydramine (50 mg 3 times daily), loratadine (10 mg daily), or terfenadine (no longer commercially available in the US) (60 mg twice daily) in controlling symptoms of seasonal or perennial allergic rhinitis (e.g., sneezing, rhinorrhea, nasal pruritus, nasal congestion, postnasal drip, itchy throat, cough, otic pruritus, ocular pruritus, tearing).1,2,3,15,20,25,26,27,41,42,49,62

Cetirizine hydrochloride 5 mg in fixed combination with pseudoephedrine hydrochloride 120 mg (i.e., Zyrtec-D^®) also was more effective than placebo in controlling symptoms of seasonal allergic rhinitis.63 In 2 randomized, double-blind, placebo-controlled studies in over 2000 patients 12 years of age and older with seasonal allergic rhinitis, treatment with the fixed-combination preparation for 2 weeks was associated with a substantial reduction in the subject-rated Total Symptom Severity Complex (TSSC) score (which included manifestations such as sneezing, runny nose, itchy nose, itchy eyes, watery eyes, postnasal drip, and nasal congestion) compared with placebo.63

In patients with allergic rhinitis and mild to moderate asthma, cetirizine improved symptoms of allergic rhinitis and did not alter pulmonary function.1,3,14,15,26 In addition, there is some evidence that asthma symptoms (e.g., self-reported chest tightness, shortness of breath, cough, sputum production) may improve during cetirizine therapy in such patients.15,26,56 Although some clinicians believe that the anticholinergic effects of some antihistamines may cause thickening of bronchial secretions resulting in further airway obstruction in asthmatics, especially those with status asthmaticus, most experts consider complete avoidance of currently available antihistamines in asthmatics unjustified.15,16,17,18,19,40,46 (See Cautions: Precautions and Contraindications in the Antihistamines General Statement 4:00.)

Cetirizine hydrochloride also is used to provide symptomatic relief in the treatment of seasonal allergic rhinitis and perennial allergic rhinitis in pediatric patients.1,2 Efficacy of the drug for symptomatic management of seasonal allergic rhinitis in children 2-11 years of age and perennial allergic rhinitis in pediatric patients 6 months to 11 years of age is based on extrapolation of the demonstrated efficacy of cetirizine in adults and the likelihood that the disease course, pathophysiology, and drug activity are substantially similar between the 2 populations.1 Safety of cetirizine in infants 6-11 or 12-24 months of age is based on placebo-controlled studies in which 0.25 mg/kg of the drug was administered twice daily for up to 7 days or 18 months, respectively; this dosage corresponds to a range of 3.4-6.2 mg daily in infants 6-11 months of age or 4-11 mg daily in those 12-24 months of age.1,64 Safety of cetirizine in children 2-5 years of age is based on placebo-controlled studies in which 0.2-0.4 mg/kg of the drug was administered daily for up to 4 weeks, whereas safety in children 6-11 years of age is based on placebo-controlled and uncontrolled clinical studies in which 5 or 10 mg of the drug was administered orally daily for up to 4 or 12 weeks, respectively.1,22,23,57,61 Recommended pediatric doses are based on cross-study comparisons1 of the pharmacokinetics and pharmacodynamics of cetirizine in adults and children1,2,11,24 and on safety profiles of the drug from studies in adults and children at recommended or higher doses.1,22,23

Chronic Idiopathic Urticaria and Other Urticarias

Cetirizine is used for self-medication 72 to provide symptomatic relief of pruritus associated with chronic idiopathic urticaria (e.g., hives).1,2,3,12,20,28,29,46 In short-term (2-6 weeks) controlled clinical trials in patients with this condition, cetirizine hydrochloride (5-20 mg daily) was more effective than placebo and at least as effective as astemizole (10 mg daily), hydroxyzine hydrochloride (25-75 mg daily), or terfenadine (60 mg twice daily) in decreasing the incidence, severity, and duration of urticaria and relieving associated pruritus.1,2,3,12,20,28,29 Limited evidence suggests that clinical benefit may not be improved substantially by the addition of a histamine H₂-receptor antagonist (e.g., cimetidine) to cetirizine therapy in patients with chronic idiopathic urticaria.21

Cetirizine also is used to provide symptomatic relief in the treatment of chronic idiopathic urticaria in pediatric patients.1 Efficacy of the drug in this condition in pediatric patients 6 months to 11 years of age is based on extrapolation of the demonstrated efficacy of cetirizine in adults and the likelihood that the disease course, pathophysiology, and drug activity are substantially similar between the 2 populations.1 Safety of cetirizine in children 2-5 years of age is based on placebo-controlled studies in which 0.2-0.4 mg/kg of the drug was administered daily for up to 4 weeks, whereas safety in children 6-11 years of age is based on placebo-controlled and uncontrolled clinical studies in which 5 or 10 mg of the drug was administered orally daily for up to 4 or 12 weeks, respectively.1 Safety of cetirizine in infants 6-11 or 12-24 months of age is based on placebo-controlled studies in which 0.25 mg/kg of the drug was administered twice daily for up to 7 days or 18 months, respectively; this dosage corresponds to a range of 3.4-6.2 mg daily in infants 6-11 months of age or 4-11 mg daily in those 12-24 months of age.1,64 Recommended pediatric doses are based on cross-study comparisons1 of the pharmacokinetics and pharmacodynamics of cetirizine in adults and children1,2,11,24 and on safety profiles of the drug from studies in adults and children at recommended or higher doses.1,22,23

Limited data indicate that cetirizine may show some benefit in the management of physical urticaria† (e.g., urticaria triggered by mechanical trauma, light, heat, cold, vibration, water), atopic dermatitis†, and insect (e.g., mosquito) bites†.2

Common Cold

Nonsedating (second generation) antihistamines do not appear to be effective in relieving rhinorrhea associated with the common cold, suggesting that histamine is not a principal mediator of this manifestation.32,37 The extent to which histamine contributes to other manifestations of the common cold currently is unclear, but pathogenesis of the full constellation of symptoms that constitute the common cold appears to be complex, involving a number of mediators and neurologic mechanisms.32,33,34,35,36

Administration

Cetirizine is administered orally.1,3 Cetirizine oral solution (syrup) should be administered using the measuring device (i.e., cup) provided by the manufacturer.70,72 Cetirizine chewable tablets may be administered with or without water.1,71 Tablets containing cetirizine hydrochloride in fixed combination with pseudoephedrine hydrochloride should be swallowed intact and patients should be instructed not to break or chew such tablets.63,69

The manufacturer states that the time of administration of cetirizine may be adjusted for individual patient requirements.1,3 Although food may decrease peak plasma concentrations of cetirizine and lengthen the time to achievement of peak plasma concentrations,1,2,3,12 the manufacturer states that cetirizine may be administered without regard to food because food does not affect the extent of absorption of the drug when administered as conventional or chewable tablets.1,2,3,12,14,20

The oral bioavailability of cetirizine hydrochloride conventional tablets is comparable to that of the oral solution and to that of the chewable tablets (administered with or without water).1

Dispensing and Administration Precautions

Because of similarities in spelling, dosage intervals (once daily), and tablet strengths (5 and 10 mg) of Zyrtec^® (cetirizine hydrochloride) and Zyprexa^® (olanzapine, an atypical antipsychotic agent), extra care should be exercised in ensuring the accuracy of prescriptions for these drugs.65 (See Cautions: Precautions and Contraindications.)

Dosage

Allergic Rhinitis and Chronic Idiopathic Urticaria

For symptomatic relief of seasonal allergic rhinitis or other upper respiratory allergies, the usual initial dosage of cetirizine hydrochloride for self-medication 68,70,71 in adults and children 6 years of age and older is 5 or 10 mg once daily, depending on symptom severity.1,2,3,15,20,22,23,25,68,70,71,72 In clinical trials, most patients 12 years of age and older had cetirizine hydrochloride therapy initiated at a dosage of 10 mg daily.1 Although dosages ranging from 5-20 mg daily have been used in patients 12 years of age and older,1,2,3,11,12,15,20,25,26,27,28,29 10 mg daily was more effective than 5 mg daily in this age group in clinical trials, and no additional benefit was observed with the 20-mg daily dosage in these trials.1 The usual dosage for self-medication 70 in pediatric patients 2 to younger than 6 years of age is 2.5 mg once daily (as an oral solution);1,70 dosage may be increased to a maximum of 5 mg administered once daily or as a 2.5-mg dose every 12 hours.1,70 When cetirizine is used in fixed combination with pseudoephedrine hydrochloride in adults and children 12 years of age and older, the usual dosage for self-medication is 5 mg of cetirizine hydrochloride every 12 hours.69

For symptomatic relief of perennial allergic rhinitis, the usual dosages of cetirizine hydrochloride in adults and children 2 years of age and older (when used under the direction of a clinician) are similar to those recommended for management of seasonal allergic rhinitis.1,2,3,15,20,22,23,25,63 The usual prescribed dosage in pediatric patients 6 months to younger than 2 years of age is 2.5 mg once daily (as an oral solution); dosage in pediatric patients 12-23 months of age may be increased to a maximum dosage of 5 mg daily, given as a 2.5-mg dose every 12 hours.1 The oral solution is the recommended formulation in children younger than 2 years of age.1 (See Cautions: Pediatric Precautions.) When cetirizine hydrochloride is used in fixed combination with pseudoephedrine hydrochloride for the symptomatic relief of perennial allergic rhinitis in adults and children 12 years of age or older, the usual dosage is 5 mg of cetirizine hydrochloride twice daily (every 12 hours).63

For the management of chronic idiopathic urticaria, the usual dosage of cetirizine hydrochloride for self-medication 72 in adults and children 6 years of age and older is 5 or 10 mg once daily, depending on symptom severity.1,72 In clinical trials, most patients 12 years of age and older had cetirizine hydrochloride therapy initiated at a dosage of 10 mg daily.1 Although dosages ranging from 5-20 mg daily have been used in patients 12 years of age and older,1,2,3,11,12,15,20,25,26,27,28,29 a dosage of 10 mg daily was more effective than 5 mg daily in this age group in clinical trials, and no additional benefit was observed with the 20-mg daily dosage in these trials.1 Although cetirizine currently is not labeled for self-medication in children younger than 6 years of age,72 the drug can be used under the direction of a clinician in children 6 months to younger than 6 years of age.1 The usual prescribed dosage in pediatric patients 2 to younger than 6 years of age is 2.5 mg once daily (as an oral solution); dosage may be increased to a maximum of 5 mg administered once daily or as a 2.5-mg dose every 12 hours.1 The usual prescribed dosage in pediatric patients 6 months to younger than 2 years of age is 2.5 mg once daily (as an oral solution); dosage in pediatric patients 12-23 months of age may be increased to a maximum dosage of 5 mg daily, given as a 2.5-mg dose every 12 hours.1

The elimination half-life of cetirizine may be prolonged and total body clearance decreased in geriatric adults compared with those in younger adults (see Pharmacokinetics: Elimination);1 therefore, the manufacturer recommends that patients 65 years of age and older receive no more than 5 mg of cetirizine hydrochloride once daily for self-medication .70,71,72 Because geriatric patients are more likely to have decreased renal function, dosage of cetirizine hydrochloride should be carefully selected in these patients and renal function monitored accordingly.1 (See Dosage and Administration: Dosage in Renal and Hepatic Impairment and see Cautions: Geriatric Precautions.)

Dosage in Renal and Hepatic Impairment

The manufacturer states that patients 12 years of age or older who have impaired renal function (e.g., creatinine clearance of 11-31 mL/minute) or hepatic impairment or who are undergoing hemodialysis (creatinine clearance of less than 7 mL/minute), should receive a cetirizine hydrochloride dosage of 5 mg daily.1,3 The manufacturer also states that children 6-11 years of age with impaired renal or hepatic function should use the lower recommended dosage (5 mg once daily).1 The manufacturer states that use of cetirizine hydrochloride in children younger than 6 years of age with impaired renal or hepatic function is not recommended because administration of doses smaller than 2.5 mg is difficult and not reliable, and pharmacokinetic data are lacking in this patient population.1

When extended-release tablets of cetirizine hydrochloride in fixed combination with pseudoephedrine hydrochloride are used in patients 12 years of age or older who have impaired renal function (i.e., creatinine clearance of 11-31 mL/minute) or hepatic impairment or who are undergoing hemodialysis (creatinine clearance of less than 7 mL/minute), the recommended cetirizine hydrochloride dosage is 5 mg once daily.63

During controlled and uncontrolled clinical trials in patients 12 years of age and older receiving oral cetirizine hydrochloride dosages of 5-20 mg daily for 1 week to 6 months (mean duration: 30 days), adverse effects were mild to moderate and the rate of discontinuance of therapy secondary to adverse effects associated with the drug was similar to that reported with placebo.1,3 Discontinuance of therapy because of adverse events was reported in 2.9% of patients receiving cetirizine compared with 2.4% of those receiving placebo.1,3,28 The incidence of adverse effects was not affected by race, age, gender, or body weight.1,3

During controlled and uncontrolled clinical trials in patients 6-11 years of age receiving oral cetirizine hydrochloride dosages of 1.25-10 mg daily for 2-12 weeks and controlled clinical trials in patients 2-5 years of age usually receiving a single 5-mg dose of cetirizine hydrochloride daily for up to 4 weeks, most adverse effects were mild to moderate, and discontinuance of therapy because of adverse events was reported in only 0.4% of the children receiving cetirizine compared with 1% of those receiving placebo.1 The incidence and nature of adverse effects in children 6-11 years of age were similar to those in children 2-5 years of age.1 In placebo-controlled studies in pediatric patients 6-11 or 12-24 months of age receiving an oral cetirizine hydrochloride dosage of 0.25 mg/kg twice daily for 7 days or 18 months, respectively, the incidences of adverse effects generally were similar in the cetirizine and placebo groups; however, certain adverse CNS effects (i.e., irritability/fussiness, insomnia) occurred more frequently in patients receiving cetirizine than in those receiving placebo.1 (See Cautions: Nervous System Effects.)

Adverse effects reported in 2% or more of patients 12 years of age and older who received cetirizine hydrochloride (as conventional tablets) at dosages up to 10 mg daily included somnolence, fatigue, dry mouth, pharyngitis, and dizziness.1,63 Adverse effects reported in 2% or more of patients 6-11 years of age who received 5-10 mg of cetirizine hydrochloride daily included headache, pharyngitis, abdominal pain, coughing, somnolence, diarrhea, epistaxis, bronchospasm, nausea, and vomiting.1

Adverse effects reported in 1% or more of patients 12 years of age and older with seasonal allergic rhinitis who received extended-release tablets of cetirizine hydrochloride in fixed combination with pseudoephedrine hydrochloride (i.e., Zyrtec-D^®) included insomnia, dry mouth, fatigue, somnolence, pharyngitis, epistaxis, accidental injury, dizziness, and sinusitis.63

Nervous System Effects

The most frequent adverse effect in patients 12 years of age and older reported during cetirizine therapy is somnolence, occurring in 11, 14, or 6% of patients receiving 5-mg doses, 10-mg doses, or placebo, respectively.1,2,3,5,6,27,28,39,41,42,43,49 Overall, somnolence has been reported in 13.7 or 6.3% of patients receiving cetirizine or placebo, respectively.1,2,3 In addition, in clinical trials in patients 6-11 years of age, somnolence occurred in 1.9, 4.2, or 1.3% of patients receiving 5-mg doses, 10-mg doses, or placebo, respectively.1 Discontinuance of therapy because of somnolence has been reported in 1 or 0.6% of patients receiving cetirizine or placebo, respectively.1,3 In patients 6-24 months of age, somnolence occurred with essentially the same frequency in those who received cetirizine versus placebo.1

Fatigue or dizziness occurred in 5.9 or 2%, respectively, of patients 12 years of age and older receiving cetirizine, whereas these effects occurred in 2.6 or 1.2%, respectively, of patients receiving placebo.1,2,3,6,28,41,49 Headache was reported in more than 2% of patients 12 years of age and older receiving the drug; however, headache occurred more frequently in patients receiving placebo.1,27,28,41,42,49 In clinical trials in patients 6-11 years of age, headache occurred in 11, 14, or 12.3% of patients receiving 5-mg doses, 10-mg doses, or placebo, respectively.1 Abnormal coordination, ataxia, confusion, abnormal thinking, agitation, amnesia, anxiety, depersonalization, depression, emotional lability, euphoria, impaired concentration, insomnia, sleep disorders, nervousness, paroniria, dysphonia, asthenia, malaise, pain, hyperesthesia, hypoesthesia, hyperkinesia, hypertonia, migraine headache, myelitis, paralysis, paresthesia, ptosis, syncope, tremor, twitching, and vertigo have been reported in less than 2% of patients 12 years of age and older and children 6-11 years of age receiving cetirizine hydrochloride; however, a causal relationship to the drug has not been established.1 Aggressive reaction, seizures, hallucinations, suicidal ideation, and suicide have been reported rarely during postmarketing surveillance.1,63

In a controlled study of 1 week's duration in patients 6-11 months of age, those receiving cetirizine exhibited greater irritability/fussiness than those receiving placebo.1 In a controlled study in patients 12 months of age and older, insomnia occurred more frequently with cetirizine than with placebo (9 vs 5.3%, respectively).1 In those who received 5 mg or more daily, fatigue occurred in 3.6 or 1.3% and malaise in 3.5 or 1.8% of those receiving cetirizine or placebo, respectively.1

Oronasopharyngeal and Pulmonary Effects

Dry mouth or pharyngitis occurred in 5 or 2%, respectively, of those receiving cetirizine, whereas these effects occurred in 2.3 or 1.9%, respectively, of those receiving placebo.1,3,20,28,41,49 In clinical trials in patients 6-11 years of age, pharyngitis, coughing, bronchospasm, or epistaxis occurred in 6.2, 4.4, 3.1, or 3.7%, respectively, of children receiving 5-mg doses of the drug; in 2.8, 2.8, 1.9, or 1.9%, respectively, of children receiving 10-mg doses of the drug; and in 2.9, 3.9, 1.9, or 2.9%, respectively, of children receiving placebo.1

Bronchitis, dyspnea, hyperventilation, increased sputum, pneumonia, respiratory disorder, rhinitis, nasal polyp, sinusitis, upper respiratory tract infection, increased salivation, discoloration and/or edema of the tongue, and aggravated dental caries have been reported in less than 2% of patients 12 years of age and older and children 6-11 years of age receiving cetirizine hydrochloride; however, a causal relationship to the drug has not been established.1 Orofacial dyskinesia also has been reported.1

GI Effects

In clinical trials in patients 6-11 years of age, abdominal pain, diarrhea, nausea, or vomiting occurred in 4.4, 3.1, 1.9, or 2.5%, respectively, of children receiving 5-mg doses of the drug; in 5.6, 1.9, 2.8, or 2.3%, respectively, of children receiving 10-mg doses of the drug; and in 1.9, 1.3, 1.9, or 1%, respectively, of children receiving placebo.1 Nausea was reported in more than 2% of patients 12 years of age and older receiving cetirizine; however, nausea occurred more frequently in patients receiving placebo.1

Anorexia, increased appetite, taste loss, taste perversion, dyspepsia, gastritis, stomatitis (including ulcerative stomatitis), enlarged abdomen, eructation, flatulence, constipation, melena, rectal hemorrhage, and hemorrhoids have been reported in less than 2% of patients 12 years of age and older and children 6-11 years of age receiving cetirizine hydrochloride; however, a causal relationship to the drug has not been established.1

Cardiovascular Effects

Palpitation, tachycardia, hypertension, chest pain, facial edema, generalized edema, leg edema, peripheral edema, hot flashes, or cardiac failure has been reported in less than 2% of patients 12 years of age and older and children 6-11 years of age receiving cetirizine hydrochloride; however, a causal relationship to the drug has not been established.1

Although serious cardiac effects, including ventricular fibrillation and death associated with prolonged QT interval and atypical ventricular tachyarrhythmia (torsades de pointes), have been reported in patients receiving certain other second generation antihistamines (e.g., astemizole [no longer commercially available in the US], terfenadine [no longer commercially available in the US]), administration of cetirizine hydrochloride alone to healthy adult men at dosages of 60 mg daily (6 times the maximum recommended daily dosage) for 1 week has not been associated with significant prolongation of the QT interval corrected for rate (QT_c).1,2,3,4,29,30,31 In addition, in placebo-controlled studies in pediatric patients 6-11 months or 6-11 years of age who received a cetirizine hydrochloride dosage of 0.25 mg/kg twice daily or 5-10 mg daily, respectively, there was no significant prolongation of the QT_c interval compared with baseline measurements or placebo after 1 or 2 weeks, respectively.1,57 Similar findings were reported in other studies in which cetirizine was administered to infants 6-23 months of age.1 The effect of cetirizine hydrochloride on the QT_c interval in children younger than 12 years of age receiving dosages exceeding 10 mg has not been studied.1

The manufacturer states that concomitant administration of cetirizine hydrochloride with drugs known to inhibit cytochrome P-450 microsomal enzymes (e.g., azithromycin, erythromycin, ketoconazole) has not been associated with clinically important changes in ECG parameters (e.g., QT_c intervals) and that no clinically important interactions have been reported in patients receiving cetirizine concomitantly with azithromycin, erythromycin, or ketoconazole.1,3,31,56,57 (See Drug Interactions: Drugs Affecting Hepatic Microsomal Enzymes.)

Genitourinary and Renal Effects

Cystitis, dysuria, hematuria, micturition frequency, polyuria, urinary incontinence, urinary retention, urinary tract infection, dysmenorrhea, intermenstrual bleeding, leukorrhea, menorrhagia, decreased libido, or vaginitis has been reported in less than 2% of patients 12 years of age and older and children 6-11 years of age receiving cetirizine hydrochloride; however, a causal relationship to the drug has not been established.1 Glomerulonephritis also has been reported.1

Dermatologic and Sensitivity Reactions

Acne, dermatitis, dry skin, eczema, rash (which may be erythematous), urticaria, skin disorder, skin nodules, purpura, bullous eruption, furunculosis, hyperkeratosis, hypertrichosis, alopecia, seborrhea, pruritus, purpura, photosensitivity reactions (which may be toxic), or angioedema has been reported in less than 2% of patients 12 years of age and older and children 6-11 years of age receiving cetirizine hydrochloride; however, a causal relationship to the drug has not been established.1 Anaphylaxis also has been reported.1

Ocular and Otic Effects

Visual field defect, blindness, conjunctivitis, ocular pain, glaucoma, loss of ocular accommodation, ocular hemorrhage, periorbital edema, xerophthalmia, deafness, otalgia, ototoxicity, or tinnitus has been reported in less than 2% of patients 12 years of age and older and children 6-11 years of age receiving cetirizine hydrochloride; however, a causal relationship to the drug has not been established.1

Hepatic Effects

Transient, reversible elevations of hepatic aminotransferases (transaminases) occurred during cetirizine therapy.1,3,4 In addition, hepatitis with substantial elevations of aminotransferases and bilirubin has been associated with the use of cetirizine.1

Other Adverse Effects

Accidental injury, back pain, fever, increased weight, cholestasis, pallor, rigors, lymphadenopathy, hemolytic anemia, thrombocytopenia, breast pain in women, or parosmia has been reported in less than 2% of patients 12 years of age and older and children 6-11 years of age receiving cetirizine hydrochloride; however, a causal relationship to the drug has not been established.1

No cases of drug abuse or dependence have been reported with cetirizine hydrochloride to date.1,56

Precautions and Contraindications

The incidence of adverse effects associated with cetirizine use generally appears to be less than that associated with the use of first generation (prototypical, sedating) antihistamines, although evidence from some clinical studies indicates that the incidence of somnolence associated with cetirizine may be higher than that associated with other second generation antihistamines (e.g., loratadine).2,56 (See Nervous System Effects in Pharmacology and also in Cautions.) In addition, effects similar to those occurring in patients receiving first generation antihistamines have been reported, and the potential for typical adverse effects induced by these antihistamines should be considered during cetirizine therapy.56 Pharmacologic studies indicate that cetirizine does not have appreciable anticholinergic effects, although dry mouth has been reported in clinical studies more frequently with the drug than with placebo.1,3,20,28,41,49

Because somnolence1,2,3,5,6,27,28,39,41,42,43,49 has been reported in some individuals in clinical studies, patients should be warned that the drug may impair their ability to perform hazardous activities requiring mental alertness or physical coordination (e.g., operating machinery, driving a motor vehicle).1,3 In addition, patients should be warned that additive CNS depression may occur when cetirizine is administered concomitantly with other CNS depressants (e.g., alcohol, sedatives, tranquilizers)1,3,68,69,70,71,72 and should be advised to avoid such concomitant use.1

Patients with chronic hepatic impairment, patients with moderate renal impairment (creatinine clearance of 11-31 mL/minute), patients undergoing hemodialysis, and geriatric patients have decreased clearance of the drug1,3,20,39,46,60 and should be given a lower dosage of cetirizine.1,3,63,70,71,72

Patients receiving the fixed combination of cetirizine hydrochloride and pseudoephedrine hydrochloride for self-medication should be advised to consult a clinician before initiating therapy if they have renal or hepatic impairment, heart disease, hypertension, thyroid disease, diabetes mellitus, glaucoma, or difficulty in urination resulting from enlargement of the prostate.69 If the fixed-combination preparation is used, other precautions and contraindications associated with pseudoephedrine also must be considered.63,69 (See Pseudoephedrine Hydrochloride 12:12.12.)

Patients receiving cetirizine should be instructed to take the drug only as needed and not to exceed the recommended dosage.69

Patients receiving cetirizine in fixed combination with pseudoephedrine hydrochloride for self-medication should be instructed to discontinue therapy and contact their clinician if symptoms do not improve within 7 days or are accompanied by fever, or if nervousness, dizziness, or sleeplessness occurs.69

Patients receiving cetirizine as self-medication for management of chronic idiopathic urticaria (e.g., hives) should be informed that the drug does not prevent hives resulting from any known cause (e.g., food, drug, insect sting, latex or rubber gloves), and that avoidance of the cause is the only way to prevent occurrence of this dermatologic reaction.72 Prior to initiating cetirizine therapy, patients should consult a clinician if they have hives that are unusual in color, that look bruised or blistered, or that do not itch.72 Patients should be warned that hives may present with other severe allergic reactions, including anaphylactic shock (e.g., trouble swallowing, swelling of the tongue, trouble speaking, wheezing or trouble breathing, dizziness or loss of consciousness, swelling in or around the mouth, drooling).72 These manifestations may occur when hives first appear or up to several hours later and can be life-threatening if not treated immediately.72 If anaphylactic shock occurs in conjunction with hives, patients should be advised to seek emergency help immediately.72 Patients should be instructed to discontinue cetirizine therapy and contact their clinician if manifestations of chronic idiopathic urticaria do not improve within 3 days or if the hives have persisted for more than 6 weeks.72 In addition, patients who have been prescribed an epinephrine auto-injector for management of anaphylaxis or severe allergic reactions associated with chronic idiopathic urticaria should be advised to carry the epinephrine auto-injector at all times; cetirizine should not be used as a substitute for this device.72

Patients should be advised to discontinue cetirizine therapy immediately and to contact their clinician if any signs of an allergic reaction occur.69,70,71,72 (See Cautions: Dermatologic and Sensitivity Reactions.)

Because of similarities in spelling, dose intervals (once daily), and tablet strengths (5 and 10 mg) of Zyrtec^® (the trade name for cetirizine hydrochloride) and Zyprexa^® (the trade name for olanzapine, an atypical antipsychotic agent), several dispensing or prescribing errors have been reported to the manufacturer of Zyprexa^® (Lilly).65 These medication errors may result in unnecessary adverse events or a potential relapse in patients with schizophrenia or bipolar disorder.65 Therefore, the manufacturer of Zyprexa^® cautions that extra care should be exercised in ensuring the accuracy of written prescriptions for Zyrtec^® and Zyprexa^® such as printing both the proprietary (brand) and nonproprietary (generic) names on all prescriptions for these drugs.65 The manufacturer also recommends that pharmacists assess various measures of avoiding dispensing errors and implement them as appropriate (e.g., placing drugs with similar names apart from one another on pharmacy shelves, patient counseling).65

Cetirizine is contraindicated in patients who are hypersensitive to cetirizine, hydroxyzine, or any ingredient in the formulation.1,3,63,68,69,70,71,72

Pediatric Precautions

Safety of cetirizine hydrochloride in pediatric patients 6 months to 5 years of age is based on controlled clinical trials, and safety in children 6-11 years of age is based on both controlled and uncontrolled trials.1 47 (See Uses.) Efficacy of cetirizine for the treatment of perennial allergic rhinitis and chronic idiopathic urticaria in pediatric patients 6 months to 11 years of age and for seasonal allergic rhinitis in pediatric patients 2-11 years of age is based on extrapolation of demonstrated efficacy in adults and the likelihood that the disease course, pathophysiology, and the drug's effect are substantially similar between these populations.1 The manufacturer states that safety and efficacy of cetirizine in children younger than 6 months of age have not been established.1 Cetirizine hydrochloride oral solution is the recommended formulation for children younger than 2 years of age.1

Results of placebo-controlled studies in pediatric patients 6-11 months or 6-11 years of age indicate that there is no significant prolongation of the QT_c interval associated with cetirizine use compared with baseline measurements or placebo.1 Similar findings were reported in other studies in which cetirizine was administered to pediatric patients 6-23 months of age.1 The effect of cetirizine hydrochloride on the QT_c interval in children younger than 12 years of age receiving dosages exceeding 10 mg has not been studied.1 (See Cautions: Cardiovascular Effects.)

The dose of pseudoephedrine hydrochloride in fixed combination with cetirizine hydrochloride exceeds the recommended dose in children younger than 12 years of age.63 In addition, safety and efficacy of this fixed combination have not been established in children younger than 12 years of age, and use of the fixed-combination preparation (e.g., Zyrtec-D^®) is not recommended in this age group.63

Overdosage and toxicity (including death) have been reported in children younger than 2 years of age receiving nonprescription (over-the-counter, OTC) preparations containing antihistamines, cough suppressants, expectorants, and nasal decongestants alone or in combination for relief of symptoms of upper respiratory tract infection.66,67 Clinicians should ask caregivers about use of nonprescription cough and cold preparations to avoid overdosage. For additional information on precautions associated with the use of cough and cold preparations in pediatric patients, see Cautions: Pediatric Precautions in the Antihistamines General Statement 4:00.

Geriatric Precautions

Safety and efficacy of cetirizine in geriatric patients have not been specifically studied to date; however, in clinical trials of cetirizine for the treatment of seasonal allergic rhinitis, perennial allergic rhinitis, or chronic urticaria involving over 3900 patients, 186 patients were 65 years and older, and 39 patients were 75 years and older.1 Although no overall differences were observed between geriatric and younger patients in the type or frequency of adverse effects in clinical trials, the possibility that some older patients may exhibit increased sensitivity to the drug cannot be ruled out.1 With regard to efficacy, clinical trials of cetirizine for each studied indication did not include sufficient numbers of patients 65 years and older to determine whether they respond differently than younger adults.1

Because geriatric patients frequently have decreased renal function, cetirizine hydrochloride dosage should be selected with caution, and it may be useful to monitor renal function in these patients.1,63 The elimination half-life of cetirizine was prolonged and total body clearance decreased in one study in a limited number of geriatric adults (mean age: 77 years) compared with those in younger adults (mean age: 53 years) (see Pharmacokinetics: Elimination). Therefore, the manufacturer recommends that patients 77 years of age and older receive a lower cetirizine hydrochloride dosage.1 (See Dosage and Administration: Dosage.)

Clinical trials of cetirizine hydrochloride in fixed combination with pseudoephedrine hydrochloride did not include sufficient numbers of patients 65 years and older to determine whether they respond differently than younger adults.63 However, geriatric patients may be especially sensitive and are more likely to have adverse effects from administration of sympathomimetic amines than younger patients.63 For further information about the effects of pseudoephedrine in geriatric patients, see Cautions: Precautions and Contraindications in Pseudoephedrine Hydrochloride 12:12.12.

Mutagenicity and Carcinogenicity

Cetirizine was not mutagenic in the Ames test and was not clastogenic in the human lymphocyte, mouse lymphoma, and in vivo rat micronucleus assays.1

No evidence of carcinogenic potential was observed in a 2-year study in rats receiving oral cetirizine hydrochloride dosages up to 20 mg/kg daily (approximately 15 or 7 times the maximum recommended daily oral dosage in adults or infants, respectively, on a mg/m² basis).1,57 In mice receiving oral cetirizine hydrochloride dosages of 16 mg/kg daily (approximately 6 or 3 times the maximum recommended daily oral dosage in adults or infants, respectively, on a mg/m² basis) for 2 years, there was an increased incidence of benign liver tumors in male mice.1,57 However, no increased incidence in liver tumors was observed in mice receiving oral cetirizine dosages of 4 mg/kg daily (approximately 2 times the maximum recommended daily oral dosage in adults and approximately equivalent to the maximum recommended oral dosage in infants on a mg/m² basis).1,57 The clinical importance of these findings during long-term use of cetirizine is not known.1

Pregnancy, Fertility, and Lactation

Pregnancy

Reproduction studies in mice, rats, and rabbits using oral cetirizine hydrochloride dosages up to 96, 225, and 135 mg/kg daily, respectively (approximately 40, 180, and 220 times, respectively, the maximum recommended daily oral dosage in adults on a mg/m² basis), have not revealed evidence of teratogenicity.1,3,57 Because there are no adequate and controlled studies to date using cetirizine in pregnant women and animal studies are not always predictive of human response, cetirizine hydrochloride should be used during pregnancy only when clearly needed.1,3

Cetirizine hydrochloride in combination with pseudoephedrine has been shown to increase the number of fetal skeletal malformations (rib distortions) and variants (unossified sternebrae) in rats when given orally in a fixed-combination ratio at a dosage of 6/154 mg/kg (approximately 5 times the maximum recommended adult dosage on a mg/m² basis).63 These effects were not observed at a dosage of 1.6/38 mg/kg (approximately the maximum recommended adult dosage on a mg/m² basis).63 Reproduction studies in rabbits using cetirizine hydrochloride and pseudoephedrine hydrochloride in a fixed-combination ratio at a dosage of up to 6/154 mg/kg (approximately 10 times the maximum recommended adult dosage on a mg/m² basis) have not revealed evidence of harm to the fetus.63 There are no adequate and controlled studies to date using cetirizine hydrochloride and pseudoephedrine hydrochloride in pregnant women, and the fixed combination should be used during pregnancy only when the potential benefits justify the possible risks to the fetus.63

Fertility

In a fertility and general reproductive performance study in mice, oral cetirizine hydrochloride did not impair fertility at dosages of 64 mg/kg daily (about 25 times the maximum recommended daily dosage in adults on a mg/m² basis).1,57 In a reproductive study in rats, oral cetirizine hydrochloride and pseudoephedrine did not impair fertility in a fixed combination at a dosage of 6/154 mg/kg (approximately 5 times the maximum recommended adult dosage on a mg/m² basis.63

Lactation

In lactating beagles, about 3% of a cetirizine dose was distributed in milk.1 In mice, cetirizine caused retarded pup weight gain during lactation when dams were receiving a cetirizine hydrochloride dosage of 96 mg/kg daily (about 40 times the maximum recommended daily dosage in adults on a mg/m² basis).1 In rats, cetirizine hydrochloride and pseudoephedrine hydrochloride caused retarded pup weight gain and decreased viability during lactation when administered orally to dams in fixed combination at a dosage of 6/154 mg/kg (approximately 5 times the maximum recommended adult dosage on a mg/m² basis) but not when administered at a dosage of 1.6/38 mg/kg (approximately the maximum recommended adult dosage on a mg/m² basis).63 Cetirizine is distributed into human milk.1,63 Pseudoephedrine also distributes into human milk.63 Therefore, use of cetirizine hydrochloride alone or in combination with pseudoephedrine hydrochloride in nursing women is not recommended.1,3,57,63,68,69,70,71,72

Because cetirizine is metabolized only minimally in the liver and is excreted mainly unchanged in urine, the drug may have a low potential for adverse drug interactions associated with metabolic enzyme systems.2

Drugs Affecting Hepatic Microsomal Enzymes

Concomitant administration of cetirizine hydrochloride with drugs known to inhibit cytochrome P-450 microsomal enzymes (e.g., azithromycin, erythromycin, ketoconazole) has not been associated with clinically important changes in ECG parameters (e.g., QT_c intervals), and no clinically important interactions have been reported in patients receiving cetirizine concomitantly with azithromycin, erythromycin, or ketoconazole.1,3,31,56 Although concomitant administration of cetirizine hydrochloride (20 mg daily) with ketoconazole (400 mg daily) has been associated with prolongation of the QT_c interval (with an increase of 17.4 msec), such increase is not considered clinically important.1,56,57

CNS Depressants

Concomitant use of cetirizine hydrochloride with CNS depressants (e.g., alcohol, sedatives, tranquilizers) may result in additive CNS depression (e.g., increased drowsiness);1,3,68,69,70,71,72 therefore, such concomitant use should be avoided.1

Other Drugs

No interactions were observed in pharmacokinetic interaction studies when cetirizine was used concomitantly with pseudoephedrine or antipyrine.1,3 A 16% decrease in the clearance of cetirizine was observed in a multiple-dose study when theophylline (400 mg given once daily for 3 days) was administered with cetirizine hydrochloride (20 mg given once daily for 3 days); disposition of theophylline was not altered by the concomitant administration with cetirizine.1,3

Because monoamine oxidase (MAO) inhibitors potentiate the pressor effects of sympathomimetic drugs (e.g., pseudoephedrine), fixed-combination extended-release tablets containing cetirizine hydrochloride and pseudoephedrine hydrochloride are contraindicated in patients receiving an MAO inhibitor, or for 2 weeks after discontinuance of an MAO inhibitor.63 For further information about drug interactions with pseudoephedrine, see Drug Interactions in Pseudoephedrine Hydrochloride 12:12.12.

Acute Toxicity

Pathogenesis

The acute lethal dose of cetirizine in humans is not known.1,57 The acute minimal lethal dose is 237 mg/kg in mice (approximately 95 or 40 times the maximum recommended daily oral dosage in adults or infants, respectively, on a mg/m² basis) and 562 mg/kg in rats (approximately 460 or 190 times the maximum recommended daily oral dosage in adults or infants, respectively, on a mg/m² basis).1 In rodents, the target of acute toxicity was the CNS, and the target of multiple-dose toxicity was the liver.1

Manifestations

Overdosage has been reported in individuals receiving cetirizine.1 Somnolence was reported in one adult who ingested 150 mg of cetirizine hydrochloride; no other adverse effects, including clinical manifestations, abnormal blood chemistry, or abnormal hematology, occurred in this individual.1 Restlessness and irritability followed by drowsiness were reported in an 18-month old child who ingested about 180 mg of cetirizine hydrochloride.1

Treatment

In acute cetirizine overdosage, treatment should include symptomatic and supportive measures, taking into account the possibility of any concomitantly ingested drugs.1 There is no specific antidote for overdosage of cetirizine.1 The drug is not effectively removed by dialysis, and therefore, dialysis would not be effective in acute overdosage of cetirizine, unless a drug that is removed by dialysis were ingested concomitantly.1

Pharmacology

Cetirizine is a long-acting antihistamine.1,2,3,12 The drug has been characterized as a selective, peripheral H₁-receptor antagonist.1,2,3,6,14,20,47,48 The pharmacology of cetirizine resembles that of other currently available antihistamines.56,57 Cetirizine is the carboxylic acid metabolite of hydroxyzine.1,2,3,11,12,20 The increased polarity of cetirizine (compared with hydroxyzine)2 may decrease distribution of the drug into the CNS,1,2,3 resulting in reduced potential for adverse CNS effects compared with some first generation antihistamines (e.g., diphenhydramine, hydroxyzine).2,5,6,56,58 However, it appears that the incidence of certain adverse CNS effects (e.g., somnolence) is higher in patients receiving cetirizine than in those receiving other second generation antihistamines (e.g., loratadine).2,56

Antihistaminic Effects

In animals and humans, the antihistaminic effect of cetirizine (as measured by suppression of the wheal and flare response induced by intradermal injection of histamine) is comparable to that of astemizole (no longer commercially available in the US), clemastine, chlorpheniramine, diphenhydramine, hydroxyzine, loratadine, pyrilamine, and terfenadine (no longer commercially available in the US).2,3,20,43 Experimental evidence indicates that the drug exhibits a specific and selective antagonism of histamine H₁-receptors.1,2,3 The manufacturer states that results from several experimental models indicate that cetirizine has inhibitory effects on the acute early phase of immediate hypersensitivity response mediated by the action of H₁-receptors.3 Results of in vitro studies indicate that cetirizine has no measurable affinity for receptors other than histamine H₁-receptors, including calcium-channel blocking receptors, α₁-adrenergic receptors, or dopamine D₂ receptors.1,2,3 Unlike many other currently available antihistamines, cetirizine does not possess appreciable anticholinergic or antiserotonergic effects,56,57 although the incidence of dry mouth in clinical trials was higher in patients receiving cetirizine than in those receiving placebo.1,3,20,28,41,49

Whereas decreased efficacy (subsensitivity, tolerance), including decreased inhibition in skin reactivity to allergen or histamine, may occur within days or weeks of initiation of therapy with first generation antihistamines,55 tolerance to the effects of cetirizine usually does not occur.2 In a 5-week study in children with allergic rhinitis, tolerance to the effects of cetirizine involving histamine skin tests was not reported, and tolerance also did not occur in patients with physical urticarias who were receiving cetirizine for 8-110 weeks.2 However, in a limited number of patients, the PC₂₀ value (the concentration of histamine required to produce a 20% decrease in forced expiratory volume in 1 second [FEV₁]) declined from 118 mmol/L after a single 15-mg dose of cetirizine hydrochloride to 53 mmol/L after administration of 15 mg of cetirizine hydrochloride twice daily for 1 week, although PC₂₀ values after 1 week of therapy with cetirizine in such patients remained substantially greater than in patients receiving placebo.2

Respiratory Effects

In animals, cetirizine inhibits histamine-induced nasal airway resistance, and such inhibition appears to be comparable to that of chlorpheniramine.2,11 Results of a double-blind, randomized, comparative study in patients with allergic rhinitis indicate that response to nasally inhaled histamine was reduced substantially more by cetirizine than by placebo.45 In addition, 1.5 and 4 hours after oral administration of the drugs, 10-mg doses of cetirizine hydrochloride were at least as effective as 10-mg doses of loratadine in inhibiting histamine-induced nasal airway resistance.45 In patients with mild asthma, cetirizine hydrochloride doses of 5-20 mg had a protective effect against nebulized histamine-induced bronchospasm; oral cetirizine may attenuate substantially histamine-induced decreases in FEV₁.1,2,3,14,44 Cetirizine also had a protective effect against allergen-induced bronchospasm in patients with allergic asthma; however, such effect was observed only against the late allergic reaction and not against the early allergic reaction.40

Nervous System Effects

In vitro, cetirizine exhibits an affinity for histamine H₁-receptors from brain to peripheral tissues similar to that of terfenadine;3 however, in vivo, unlike prototypical (first generation) antihistamines, cetirizine (probably because of the polarity of the drug) does not readily cross the blood-brain barrier1,2,3 and, therefore, does not appear to interact appreciably with H₁-receptors within the CNS at usual doses.2,56,57,58 In some clinical trials, the incidence of certain CNS effects (e.g., somnolence) was higher in patients receiving cetirizine than in those receiving placebo.1,2,3,20,27,28,39,41,43,49 In addition, some data indicate that the incidence of other CNS effects (e.g., EEG disturbances, impaired psychomotor performance) may be higher in patients receiving cetirizine than in those receiving other second generation antihistamines (e.g., loratadine).2,56,59

In part, adverse CNS effects of cetirizine reported in these studies may have resulted from use of higher than recommended dosages, indicating a correlation between dose of cetirizine hydrochloride and its description as a nonsedating antihistamine.56,59 In several other studies, the CNS effects of cetirizine did not differ from those of placebo or other second generation antihistamines (e.g., astemizole) or, alternatively, no adverse CNS effects were reported with the drug.5,56,58 However, in controlled clinical trials in patients receiving 5- or 10-mg daily dosages of the drug or placebo, the overall incidence of somnolence was 13.7 or 6.3% in patients receiving cetirizine or placebo, respectively.1,2,3 (See Cautions: Nervous System Effects.)

Cardiac Effects

Although serious cardiac effects, including ventricular fibrillation and death associated with prolonged QT interval and atypical ventricular arrhythmia (torsades de pointes), have been reported in patients receiving certain other second generation antihistamines (e.g., astemizole, terfenadine), administration of cetirizine hydrochloride alone to healthy adult men at dosages of up to 60 mg daily (6 times the maximum daily dosage) for 1 week has not been associated with clinically important prolongation of the QT interval corrected for rate (QT_c).1,2,3,4,29,30,31 (See Cautions: Cardiovascular Effects.) In animals, cetirizine dosages up to 500 times the recommended clinically effective dosage were not associated with important changes in ECG parameters (e.g., QT_c intervals).4

Other Effects

Cetirizine may inhibit mediators other than histamine, including those that release histamine.1 In one study, cetirizine inhibited cold-induced urticaria in cold-challenged patients.1,3

Cetirizine appears to have some activity against allergic inflammation mediators.1,3,14,20 In studies conducted for up to 12 hours following cutaneous antigen challenge, the late phase recruitment of eosinophils, neutrophils, and basophils (components of allergic inflammatory response) was inhibited by 20-mg doses of cetirizine hydrochloride.1,3,14,20

Pharmacokinetics

The effect of gender on the pharmacokinetics of cetirizine hydrochloride has not been fully elucidated.1 In addition, pharmacokinetic studies have not revealed race-related differences in the pharmacokinetics of the drug.1

Absorption

Cetirizine hydrochloride is rapidly absorbed from the GI tract following oral administration.12,14,47,48 The bioavailability of the conventional tablets appears to be comparable to that of the oral solution or chewable tablets (whether administered with or without water).1 Following oral administration of 10- or 20-mg doses of cetirizine hydrochloride (tablets or oral solution) in healthy adults, peak plasma concentrations of 257-384 or 580 ng/mL, respectively, are achieved in about 1 hour;1,2,3,4,14,39,46,47,48 following administration of cetirizine hydrochloride chewable tablets, peak plasma concentrations also are achieved within 1 hour.1 Considerable interindividual variation in peak plasma concentrations of cetirizine does not appear to occur.3,48 In healthy individuals receiving 10 mg of cetirizine hydrochloride daily for 10 days, apparent steady-state plasma concentrations of the drug reportedly were achieved by the second day of administration.3 With multiple daily dosing, steady-state plasma concentrations averaging approximately 311 ng/mL (range: 271-351 ng/mL) usually were achieved within 1 hour (range: 0.5-1.5 hours) after administration of a dose and there was minimal accumulation of drug.1,3,39 Pharmacokinetics of the drug appear to be linear for oral doses ranging from 5-60 mg, with plasma concentrations of the drug increasing proportionately with increasing doses.1,3,4,14

Administration of cetirizine hydrochloride and pseudoephedrine hydrochloride as fixed-combination extended-release tablets reportedly does not affect the bioavailability of either drug substantially.63 Following oral administration of a single 5-mg dose of cetirizine hydrochloride (given as an extended-release tablet in fixed combination with pseudoephedrine hydrochloride 120 mg), mean peak plasma cetirizine concentration of 114 ng/mL was reached in about 2.2 hours.63 Following multiple-dose administration of the 12-hour fixed-combination tablet (at a cetirizine hydrochloride dosage of 5 mg twice daily for 7 days) in healthy individuals, steady-state peak plasma concentrations of cetirizine reportedly averaged 178 ng/mL.63

Following oral administration of cetirizine hydrochloride 5-mg oral capsules in children 7-12 years of age, peak plasma concentration of the drug averaged 275 ng/mL, whereas peak plasma concentration of the drug averaged 660 ng/mL in children 2-5 years of age receiving a 5-mg oral dose of the drug.1 The manufacturer states that the area under the plasma concentration-time curve (AUC) and peak plasma concentrations in children 2-5 and 6-11 years of age receiving 5- and 10-mg doses of cetirizine hydrochloride, respectively, were estimated to be intermediate between those observed in adults receiving single 10- and 20-mg doses of the drug.1 Following oral administration of a single cetirizine hydrochloride dose of 0.25 mg/kg in a limited number of children 6-24 months of age, peak plasma concentrations of 390 ng/mL (range: 255-525 ng/mL) were achieved in about 2 hours (range: 0.7-3.3 hours).1,47 The average AUC in pediatric patients 6 months to less than 2 years of age receiving dosages of 2.5 mg twice daily is expected to be 2-fold higher than that observed in adults receiving a dosage of 10 mg once daily.1 The manufacturer states that the AUC and peak plasma concentrations in pediatric patients 6-23 months of age receiving a single 0.25 mg/kg dose (mean: 2.3 mg) of cetirizine hydrochloride were estimated to be intermediate between those observed in adults receiving single 10- and 20-mg doses of the drug.1

Peak plasma concentrations and AUCs may be increased in geriatric adults (mean age: 77 years).3 Following administration of a 10-mg dose of cetirizine hydrochloride in geriatric adults, peak plasma concentrations of 460 ng/mL were achieved in about 0.9 hours.3 Peak plasma concentrations, time to achieve peak plasma concentrations, and AUCs of cetirizine may be increased in patients with renal impairment compared with those in healthy individuals.2,3 Mean peak plasma concentrations of cetirizine reportedly were 356 (range: 292-420 ng/mL) and 357 ng/mL (range: 185-529 ng/mL) in patients with mild (creatinine clearance of 42-77 mL/minute) and moderate (creatinine clearance of 11-31 mL/minute) renal impairment, respectively; time to achieve peak plasma concentrations in patients with moderate renal impairment was increased to about 2.2 hours.1,3 In addition, peak plasma concentrations and AUCs may be increased in patients with hepatic impairment.39 In one study in patients with primary biliary cirrhosis who received a single 10-mg oral dose of cetirizine hydrochloride, mean peak plasma concentrations of 498 ng/mL (range: 380-616 ng/mL) occurred within about 1 hour; cetirizine was still detectable in some patients 96 hours after dosing.39

Although food may decrease peak plasma concentrations of cetirizine (by 23, 37, or 30%, respectively, for conventional tablets, chewable tablets, or extended-release tablets in fixed combination with pseudoephedrine hydrochloride) and lengthen the time (by about 1.7, 2.8, or 1.8 hours, respectively) to achievement of peak plasma concentrations,1,2,3,12,20 food does not affect the extent of absorption (measured by the AUC) of the drug.1,2,3,12,20,63

Following oral administration of a single 10-mg dose of cetirizine hydrochloride in healthy adults, the antihistaminic effect of the drug (as measured by suppression of the wheal and flare response induced by intradermal injection of histamine) was apparent within 20 and 60 minutes in 50 and 95% of individuals, respectively, and persisted for about 24 hours.1,2,3,6,14,20,43,57 In addition, following oral administration of a single 5- or 10-mg dose of cetirizine hydrochloride in healthy children (5-10 years of age), the antihistaminic effect of the drug (as measured by suppression of the wheal and flare response induced by intradermal injection of histamine) was apparent within 20-60 minutes and persisted for at least 24 hours.1,14 In infants 7-25 months of age receiving oral cetirizine hydrochloride at a dosage of 0.25 mg/kg twice daily for 4-9 days, 90% inhibition of histamine-induced cutaneous wheal and 87% inhibition of the flare occurred 12 hours following administration of the last dose.1 The antihistaminic effect of the drug may persist longer in patients with hepatic impairment; limited data indicate that suppression of wheal and flare response persisted for 48 and 72 hours, respectively, in such patients.39 The manufacturer states that the clinical relevance of suppressing histamine-induced wheal and flare response on skin testing is unknown.1

Distribution

Distribution of cetirizine and its metabolites into human body tissues and fluids has not been fully elucidated.1,3 In animals, the drug appears to be extensively distributed into many body tissues and fluids with highest concentrations obtained in the liver, kidneys, and lungs.3 However, the volume of distribution of cetirizine is relatively low compared with that of many other H₁-receptor antagonists.20 The volume of distribution is about 0.39-0.6, 0.46, 0.54, 0.44, or 0.38-0.56 L/kg in healthy adults, patients with mild renal impairment (creatinine clearance of 42-77 mL/minute), patients with moderate renal impairment (creatinine clearance of 11-31 mL/minute), patients with hepatic impairment, or geriatric patients (mean age: 77 years), respectively.2,3,39,47

The substantial polarity of cetirizine2 apparently limits distribution of the drug into the CNS.1,2,3,6,20,46 Animal studies indicate that brain cetirizine concentrations were less than 10% of those measured in plasma.2

Cetirizine is distributed into milk in humans and animals.1 In lactating beagles, about 3% of a cetirizine dose was distributed into milk.1

Cetirizine is approximately 93% bound to plasma proteins; protein binding appears to be independent of the concentration of the drug ranging from 25-1000 ng/mL, which includes usual therapeutic plasma concentrations.1,3

Elimination

Following oral administration of a single 10-mg dose of cetirizine hydrochloride in healthy adults, the drug may undergo biphasic elimination,47,56,57 with an initial distribution half-life of about 3 hours48 and a mean terminal elimination half-life of about 8.3 hours (range: 6.5-10 hours).1,2,4,12,14,20,39,47,48,57 In pediatric patients 7-12 years, 2-5 years, or 6-23 months of age, the elimination half-life of the drug corrected for weight was 33, 33-41, or 63% shorter, respectively, than that observed in adults.1,46,47 In addition, the elimination half-life of the drug in geriatric adults (mean age: 77 years) receiving a single 10-mg oral dose of cetirizine hydrochloride was prolonged by about 50% compared with that in younger adults (mean age: 53 years).1,3,20,39,46 The manufacturer states that plasma elimination half-life of cetirizine following multiple oral doses in healthy adults is similar to that reported following a single oral dose.2

Although a small fraction of cetirizine undergoes oxidative O -dealkylation to a metabolite with negligible antihistaminic activity, the drug undergoes a low degree of first-pass metabolism in the liver.1,2,3,11,14,39,46,47,56,57 Two unidentified metabolites also were recovered from urine; however, the enzyme(s) responsible for the metabolism of the drug has not been identified.1,2,3,39,47 Following oral administration of a single 10-mg dose of cetirizine hydrochloride in healthy individuals, about 80% of the dose is excreted within 5 days, mainly (more than 50%) as unchanged drug;1,2,4,12,14,20,39,46,47,48,57 most excretion occurs within 24 hours.1,2,3,12,48

In healthy individuals, about 70 and 10% of a radiolabeled dose was recovered in urine and feces, respectively.1,2,3,14,48 Fecal excretion has not been well characterized, and it is not known whether fecal excretion of the drug represents unabsorbed drug or if the drug is excreted via biliary elimination.48,56,57 In animals, cetirizine and its metabolites undergo extensive biliary elimination.48

In healthy adults, total body clearance of cetirizine reportedly was about 53 mL/minute, whereas in children 7-12 years of age, those 2-5 years of age, or those 6-24 months of age, the apparent total body clearance corrected for weight was 33, 81-111, or 304% greater, respectively, than that observed in adults.1,47 The apparent total body clearance in geriatric adults (mean age: 77 years) receiving a single 10-mg oral dose of cetirizine hydrochloride was 33-45% lower than in younger adults (mean age: 53 years).1,3,39 The decreased apparent total body clearance in geriatric adults may be related to decreased renal function in this age group.1

Following oral administration of 10-mg doses of cetirizine hydrochloride daily for 7 days, elimination of the drug in patients with mild renal impairment (creatinine clearance of 42-77 mL/minute) appears to be similar to that in healthy adults (creatinine clearance of 89-128 mL/minute).1 Patients with moderate renal impairment (creatinine clearance of 11-31 mL/minute) receiving this dose daily for 7 days and those on hemodialysis receiving a single 10-mg dose of the drug had a threefold increase in half-life and a 70% decrease in clearance compared with those in healthy adults.1,3,20,46,60 Less than 10% of a 10-mg dose of cetirizine hydrochloride is removed by hemodialysis.1,2

Although cetirizine appears to be minimally metabolized by liver enzymes,1,11,14,20,39 a 50-85% increase in half-life and a 40-60% decrease in clearance occurred in patients with chronic hepatic impairment following oral administration of a single 10- or 20-mg dose of cetirizine hydrochloride.1,3,20,39

Chemistry and Stability

Chemistry

Cetirizine, a piperazine derivative, is a long-acting antihistamine.1,2,3,12 The drug is the carboxylic acid metabolite of hydroxyzine.1,2,3,11,12,20,48 The increased polarity of cetirizine (compared with hydroxyzine)2 may decrease distribution of the drug into the CNS,1,2,3 resulting in a reduced potential for adverse CNS effects compared with some first generation antihistamines (e.g., diphenhydramine, hydroxyzine).2,5,6,56,58

Cetirizine hydrochloride occurs as a white crystalline powder that is soluble in water.1 Commercially available cetirizine hydrochloride oral solution is a colorless to slightly yellow syrup and has a pH of 4-5.1 Cetirizine hydrochloride occurs as a racemic mixture.1

The fixed-combination tablets contain 5 mg of cetirizine hydrochloride in an immediate-release layer and 120 mg of pseudoephedrine hydrochloride in an extended-release layer that slowly releases the drug.63

Stability

Cetirizine hydrochloride oral solution and tablets should be stored at a room temperature of 20-25°C but may be exposed to temperatures ranging from 15-30°C;1,63,68,71,72 cetirizine hydrochloride oral solution also may be refrigerated at 2-8°C.1 The fixed-combination cetirizine hydrochloride and pseudoephedrine hydrochloride extended-release tablets should be stored at a controlled room temperature of 20-25°C but may be exposed to temperatures ranging from 15-30°C.63

1. Pfizer Labs. Zyrtec^® (cetirizine hydrochloride) tablets, chewable tablets, and syrup prescribing information. New York, NY; 2006 May.

2. Spencer CM, Faulds D, Peters DH. Cetirizine: a reappraisal of its pharmacological properties and therapeutic use in selected allergic disorders. Drugs . 1993; 46:1055-80.

3. Pfizer Laboratories. Zyrtec^® (cetirizine hydrochloride) tablets product monograph. New York, NY: Undated.

4. Sale ME, Barbey JT, Woosley RL et al. The electrocardiographic effects of cetirizine in normal subjects. Clin Pharmacol Ther . 1994; 56:295-301. [PubMed 7924125]

5. Schweitzer PK, Muehlbach MJ, Walsh JK. Sleepiness and performance during three- day administration of cetirizine or diphenhydramine. J Allergy Clin Immunol . 1994; 94:716-24. [PubMed 7930305]

6. Gengo FM, Dabronzo J, Yurchak A et al. The relative antihistaminic and psychomotor effects of hydroxyzine and cetirizine. Clin Pharmacol Ther . 1987; 42:265-72. [PubMed 2887328]

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