329. DRUG PROFILE

DRUG   PROFILE

Cetirizine hydrochloride

INTRODUCTION:

A potent second-generation histamine H1 antagonist that is effective in the treatment of allergic rhinitis, chronic urticaria, and pollen-induced asthma.

STRUCTURE:

IUPAC NAME: (±)[2-[4-[(4-chlorophenyl) phenyl methyl] -1-piperazinyl]ethoxy]acetic acid dihydrochloride

Synonyms:

Cetirizina [Spanish]

Cetirizinum [Latin]

Cetrizine Hcl

Pharmacologic class: Potent second-generation histamine H1 antagonist

Category: Antihistamine, Anti allergic drug

PHYSICOCHEMICAL PROFILE

Empirical formula: C₂₁H₂₅Cl N₂O₃•2HCl

Molecular weight:  461.82g/mol

Description  : White, crystalline powder 

Solubility: Soluble in water insoluble in acetone and dichloromethane

Clinical Pharmacology:

Mechanism   of   Action:   Cetirizine,   a   human   metabolite   of   hydroxyzine,   is   an antihistamine; its principal effects are mediated via selective inhibition of peripheral H₁ receptors. The antihistaminic activity of cetirizine has been clearly documented in a variety of animal and human models. In vivo and ex vivo animal models have shown negligible anticholinergic and antiserotonergic activity. In clinical studies, however, dry mouth was more common with cetirizine than with placebo. In vitro receptor binding studies have shown no measurable affinity for other than H₁ receptors.

Pharmacokinetics

Absorption: Cetirizine was rapidly absorbed with a time to maximum concentration (T_max) of approximately 1 hour following oral administration of tablets, chewable tablets or syrup in adults.  Comparable bioavailability was found between the tablet and syrup dosage forms. When healthy volunteers were administered multiple doses of cetirizine (10 mg tablets once daily for 10 days), a mean peak plasma concentration (Cmax) of 311ng/mL was observed. No accumulation was observed. Cetirizine pharmacokinetics were linear for oral doses ranging from 5 to 60 mg. Food had no effect on the extent of exposure (AUC) of the cetirizine tablet or chewable tablet, but Tmax was delayed  by1.7 hours and 2.8 hours  respectively,  and  Cmax  was  decreased  by  23%  and  37%,  respectively  in  the presence of food.

Distribution: The mean plasma protein binding of cetirizine is 93%, independent of concentration in the range of 25-1000 ng/ml, which includes the therapeutic plasma levels observed.

Metabolism: A mass balance study in 6 healthy male volunteers indicated that 70% of the  administered  radioactivity  was  recovered  in  the  urine  and  10%  in the faeces. Approximately 50% of the radioactivity was identified in the urine as unchanged drug. Most of the rapid increase in peak plasma radioactivity was associated with parent drug, suggesting a low degree of first-pass metabolism. Cetirizine is metabolized to a limited extent by oxidative O-dealkylation to a metabolite with negligible antihistaminic activity. The enzyme or enzymes responsible for this metabolism have not been identified.

Elimination: The mean elimination half life in 146 healthy volunteers across multiple pharmacokinetic studies was 8.3 hours and the apparent total body clearance for cetirizine was approximately 53 ml/min.

Pharmacodynamics:

Cetirizine hydrochloride at doses of 5 and 10 mg strongly inhibited the wheal and flare caused by intradermal injection of histamine in 19 pediatric volunteers (aged 5 to 12 years) and the activity persisted for at least 24 hours. In a 35-day study in children aged 5 to 12, no tolerance to the antihistaminic (suppression of wheal and flare response) effects of Cetirizine hydrochloride was found. In 10 infants 7 to 25 months of age who received 4 to 9 days of Cetirizine in an oral solution (0.25 mg/kg bid), there was a 90% inhibition of  histamine-induced  (10 mg/ml)  cutaneous  wheal  and  87%  inhibition  of  the  flare 12 hours after administration of the last dose. The clinical relevance of this suppression of histamine-induced wheal and flare response on skin testing is unknown.

The effects of intradermal injection of various other mediators or histamine releasers were also inhibited by cetirizine, as was response to a cold challenge in patients with cold-induced urticaria. In a four-week clinical trial in pediatric patients aged 6 to 11 years, results of randomly obtained ECG measurements before treatment and after 2 weeks of treatment showed that Cetirizine hydrochloride 5 or 10 mg did not increase QTc versus placebo.

In a one week clinical trial (N=86) of cetirizine hydrochloride syrup (0.25 mg/kg bid) compared with placebo in pediatric patients 6 to 11 months of age, ECG measurements taken within 3 hours of the last dose did not show any ECG abnormalities or increases in QTc interval in either group compared to baseline assessments. Data from other studies where Cetirizine hydrochloride was administered to patients 6-23 months of age were consistent with the findings in this study. The effects of cetirizine hydrochloride on the QTc interval at doses higher than 10 mg have not been studied in children less than 12 years of age. In a six-week, placebo-controlled study of 186 patients (aged 12 to 64 years) with allergic rhinitis  and   mild   to  moderate  asthma,  cetirizine  hydrochloride  10 mg  once  daily improved  rhinitis  symptoms  and  did  not  alter  pulmonary  function.  In  a  two-week, placebo-controlled clinical trial, a subset analysis of 65 pediatric (aged 6 to 11 years) allergic rhinitis  patients  with  asthma  showed  cetirizine  hydrochloride  did  not  alter pulmonary   function.  These  studies  support  the  safety  of  administering  cetirizine hydrochloride  to  pediatric  and  adult  allergic  rhinitis  patients  with  mild  to  moderate asthma.

Interaction Studies

Pharmacokinetic interaction studies with cetirizine in adults were conducted with pseudoephedrine, antipyrine, ketoconazole, erythromycin and azithromycin. No interactions were observed. In a multiple dose study of theophylline (400 mg once daily for 3 days) and cetirizine (20 mg once daily for 3 days), a 16% decrease in the clearance of  cetirizine was  observed. The disposition of theophylline was not altered by concomitant cetirizine administration.

Indications and usage

Seasonal Allergic Rhinitis: Cetirizine is indicated for the relief of symptoms associated with seasonal allergic rhinitis due to allergens such as ragweed, grass and tree pollens in adults and children 2 years of age and older. Symptoms treated effectively include sneezing, rhinorrhea, nasal pruritus, ocular pruritus, tearing, and redness of the eyes.

Perennial Allergic Rhinitis: Cetirizine is indicated for the relief of symptoms associated with perennial allergic rhinitis due to allergens such as dust mites, animal dander and molds in adults and children 6 months of age and older. Symptoms treated effectively include sneezing, rhinorrhea, postnasal discharge, nasal pruritus, ocular pruritus, and tearing.

Chronic Urticaria: Cetirizine is indicated for the treatment of the uncomplicated skin manifestations of chronic idiopathic urticaria in adults and children 6 months of age and older.  It  significantly  reduces  the  occurrence,  severity,  and  duration  of  hives  and significantly reduces pruritus.

Contraindications:

Cetirizine is contraindicated in those patients with a known hypersensitivity to it or any of its ingredients or hydroxyzine.

Precautions

Activities Requiring Mental Alertness: In clinical trials, the occurrence of somnolence has been reported in some patients taking cetirizine; due caution should therefore be exercised when driving a car or operating potentially dangerous machinery. Concurrent use  of  cetirizine  with  alcohol  or  other  CNS depressants  should  be  avoided  because additional reductions in alertness and additional  impairment of CNS performance may occur.

Drug-Drug Interactions: No clinically significant drug interactions have been found with theophylline at low dose azithromycin, pseudodephidrine, ketoconazoleor erythromycin. There was a small decrease in the clearance of cetirizine caused by a 400mg dose of theophylline it is possible that larger theophylline doses could have a greater effect.

Carcinogenesis, Mutagenesis and Impairment of Fertility: In a 2-year carcinogenicity study in rats, cetirizine was not carcinogenic at dietary doses up to 20 mg/kg.  In a 2-year carcinogenicity study in mice, cetirizine caused an increased incidence of benign liver tumors in males at a dietary dose of 16 mg/kg.  No increase in the incidence of liver tumors was observed in mice at a dietary dose of 4 mg/kg  (approximately 2 times the maximum recommended daily oral dose in adults on a mg/m² basis, or  approximately equivalent  to  the  maximum  recommended  daily  oral  dose  in  infants  on  a  mg/m² basis).Cetirizine was not mutagenic in the Ames test, and not clastogenic in the human lymphocyte assay, the mouse lymphoma assay, and in vivo micronucleus test in rats. In a fertility and general reproductive performance study in mice, cetirizine did not impair fertility at an oral dose of 64 mg/kg.

Pregnancy Category B: In mice, rats, and rabbits, cetirizine was not teratogenic at oral doses up to 96, 225, and 135 mg/kg, respectively (approximately 40, 180 and 220 times the maximum recommended daily oral dose in adults on a mg/m² basis). There are, however, no adequate and well-controlled studies in pregnant women.

Nursing Mothers: In mice, cetirizine caused retarded pup weight gain during lactation at an oral dose in dams of 96 mg/kg (approximately 40 times the maximum recommended daily oral dose in adults on a mg/m² basis).  Studies in beagle dogs indicated that approximately 3% of the dose was excreted in milk. Cetirizine has been reported to be excreted in human breast milk. Because many drugs are excreted in human milk, use of cetirizine in nursing mothers is not recommended.

Geriatric Use: Of the total number of patients in clinical studies of cetirizine, 186 patients were 65 years and older, and 39 patients were 75 years and older. No overall differences in safety were observed between these patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out. With regard to efficacy, clinical  studies  of  cetirizine  for  each  approved  indication  did  not  include  sufficient numbers  of  patients  aged  65  years  and  older  to  determine  whether  they  respond differently than younger patients.

Cetirizine is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

Adverse reactions

Controlled and uncontrolled clinical trials conducted in the United States and Canada included more than 6000 patients aged 12 years and older, with more than 3900 receiving cetirizine at doses of 5 to 20 mg per day. The duration of treatment ranged from 1 week to 6 months, with a mean exposure of 30 days. Most adverse reactions reported during therapy with cetirizine were mild or moderate. In placebo-controlled trials, the incidence of discontinuations due to adverse reactions in patients receiving cetirizine 5 or 10 mg was not significantly different from placebo (2.9% vs. 2.4%, respectively).The most common adverse reaction in patients aged 12 years and older that occurred more frequently on cetirizine than placebo was somnolence. The incidence of somnolence associated with cetirizine was dose related, 6% in placebo, 11% at 5 mg and 14% at 10 mg. Discontinuations due to somnolence for cetirizine were uncommon (1.0% on cetirizine vs. 0.6% on placebo). Fatigue and dry mouth also appeared to be treatment related adverse reactions. There were no differences by age, race, and gender or by body weight with regard to the incidence of adverse reactions.

Autonomic Nervous System: Anorexia, flushing, increased salivation, urinary retention.

Cardiovascular: Cardiac failure, hypertension, palpitation, tachycardia.

Central and Peripheral Nervous Systems: Abnormal coordination, ataxia, confusion, dysphonia, hyperesthesia, hyperkinesia, hypertonia, hypoesthesia, leg cramps, migraine, myelitis, paralysis,  paresthesia, ptosis, syncope, tremor, twitching, vertigo, visual field defect.

Gastrointestinal: Abnormal hepatic  function,  aggravated  tooth  caries,  constipation, dyspepsia, eructation, flatulence, gastritis, hemorrhoids, increased appetite, melena, rectal hemorrhage, stomatitis including ulcerative stomatitis, tongue  discoloration,  tongue edema.

Genitourinary: Cystitis, dysuria, hematuria, micturition frequency, polyuria, urinary incontinence, urinary tract infection.

Hearing and Vestibular: Deafness, earache, ototoxicity, tinnitus.

Metabolic/Nutritional: Dehydration, diabetes mellitus, thirst.

Musculoskeletal: Arthralgia, arthritis, arthrosis, muscle weakness, myalgia.

Psychiatric:   Abnormal thinking, agitation,  amnesia, anxiety, decreased    libido.

Respiratory      System:    Bronchitis,    dyspnea,    hyperventilation,    increased    sputum, pneumonia, respiratory disorder, rhinitis, sinusitis, upper respiratory tract infection. Reproductive: Dysmenorrhea, female breast pain, intermenstrual bleeding, leukorrhea, menorrhagia, vaginitis.

Reticuloendothelial: Lymphadenopathy.

Skin:  Acne, alopecia, angioedema, bullous eruption,  dermatitis,  dry  skin,  eczema, erythematous rash, furunculosis, hyperkeratosis, hypertrichosis, increased  sweating, maculopapular rash,  photosensitivity reaction, photosensitivity toxic reaction, pruritus, purpura, rash, seborrhea, skin disorder, skin nodule, urticaria.

Special Senses: Taste loss, tastes perversion.

Vision: Blindness, conjunctivitis, eye pain, glaucoma, loss of accommodation, ocular hemorrhage, exophthalmia.

Body as a Whole: Accidental injury, asthenia, back pain, chest pain, enlarged abdomen, face edema, fever, generalized edema, hot flashes, increased weight, leg edema, malaise, nasal polyp, pain, pallor, periorbital edema, peripheral edema, rigors.Occasional instances of transient, reversible hepatic transaminase elevations have occurred during cetirizine therapy. Hepatitis with significant transaminase elevation and elevated bilirubin in association with the use of cetirizine has been reported.

Post-Marketing Experience

In the post-marketing period, the following additional rare, but potentially severe adverse events have been reported: aggressive reaction, anaphylaxis, cholestasis, convulsions, glomerulonephritis, hallucinations, hemolytic  anemia,  hepatitis,  or facial  dyskinesia, severe hypotension, stillbirth, suicidal ideation, suicide and thrombocytopenia.

1.4.7 Dosage and administration

Cetirizine is available as 5 mg and 10 mg capsules, 5 mg and 10 mg tablets, 1 mg/ml syrup, and 5 mg and 10 mg chewable tablets which can be taken with or without water.