Histamine H1-Receptor Antagonist
Action And Clinical Pharmacology: Cetirizine, a human metabolite of hydroxyzine, is a histamine H1 receptor antagonist antiallergic compound; its principal effects are mediated via selective inhibition of peripheral H1 receptors. Cetirizine is distinguished from other histamine H1 receptor antagonists by the presence of a carboxylic acid function. This difference may be partly responsible for the selectivity of cetirizine seen in pharmacologic models and its distinctive pharmacokinetic properties in humans.
The antihistaminic activity of cetirizine has been well documented in a variety of animal and human models. In vivo animal models have shown negligible anticholinergic or antiserotonergic activity. In vitro receptor binding studies have detected no measurable affinity for other than H1 receptors. Autoradiographic studies have shown negligible penetration into the brain. Systemically administered cetirizine does not significantly occupy cerebral H1 receptors.
Cetirizine does not exacerbate asthma and is effective in a variety of histamine mediated disorders. Oral doses of 5 to 20 mg in humans strongly inhibit the skin wheal and flare response caused by the intradermal injection of histamine. The onset of activity occurs within 20 (50% of subjects) to 60 (95% of subjects) minutes and persists for at least 24 hours following a single dose. The effects of intradermal injection of various other mediators or histamine releasers as well as components of the allergic inflammatory response to cutaneous antigen challenge are also inhibited.
Randomized, multicentre, double-blind, placebo-controlled clinical trials have demonstrated the effectiveness of cetirizine in relieving the symptoms associated with seasonal allergic rhinitis, perennial allergic rhinitis and chronic idiopathic urticaria. The clinical trials have shown only weak anticholinergic effects. There is no evidence that tolerance to the antihistaminic effects of cetirizine occurs or that cetirizine has any abuse potential or dependency liability.
Objective measurements to evaluate the effects of cetirizine on the CNS at doses up to 20 mg showed no significant effects on daytime drowsiness, reaction times, mental alertness, objective CNS depression and various other tests of cognitive function compared with placebo.
Specific ECG studies in healthy volunteers at doses up to 60 mg/day (3 times the maximum clinically studied dose) for 1 week did not prolong Qtc intervals nor was there any evidence of Qtc prolongation in clinical trials which included ECG evaluations.
Cetirizine given at the maximum clinically studied dose of 20 mg daily did not prolong the QTc when given in combination with either ketoconazole 400 mg daily or erythromycin 50 mg q8h for 10 days. Moreover, cetirizine did not significantly alter the pharmacokinetics of either ketoconazole or erythromycin nor were the pharmacokinetics of cetirizine altered by either ketoconazole or erythromycin.
Pharmacokinetics: Cetirizine is rapidly absorbed after oral administration. Peak plasma levels after a 10 mg dose are approximately 300 ng/mL and occur at about 1 hour. Coadministration of cetirizine with food does not affect bioavailability as measured by AUC but absorption is delayed by about 1 hour, with 23% lower Cmax. Plasma protein binding is 93% in the concentration range observed in clinical studies. The plasma elimination half-life is approximately 8 to 9 hours and does not change with multiple dosing. Pharmacokinetics are dose independent and plasma levels are proportional to the dose administered over the clinically studied range of 5 to 20 mg.
Cetirizine is less extensively metabolized than other antihistamines and approximately 60% of an administered dose is excreted unchanged in 24 hours. The high bioavailability associated with generally low intersubject variation in blood levels is attributable primarily to low first-pass metabolism. Only one metabolite has been identified in humans – the product of oxidative dealkylation of the terminal carboxymethyl group. The antihistaminic activity of this metabolite is negligible.
Consequently, based on (1) its relatively low level of metabolic elimination, (2) no effect on corrected QT intervals at plasma concentrations 3 times the maximal therapeutic levels and (3) no apparent interactions with ketoconazole or erythromycin, cetirizine is unlikely to have clinically significant interactions with other macrolides such as clarithromycin or other imidazole antifungals such as itraconazole in patients with normal renal and hepatic function. Although no data with these other drugs are available at the present time, there is no epidemiological evidence (safety database comprised 6 490 patients evaluated in U.S. and Canadian studies) of interactions between macrolide antibiotics and/or imidazole antifungals taken orally, and cetirizine/hydroxyzine. The epidemiological data do not suggest an increase in adverse events, cardiac or noncardiac, in patients treated with cetirizine and concomitant macrolide or imidazole antifungal medication.
In patients with mild to moderate hepatic and renal impairment, total body clearance of cetirizine is reduced and AUC and half-life increased 2- to 3-fold. Clearance is reduced in proportion to the decline in creatinine clearance. Plasma levels are unaffected by hemodialysis. The plasma elimination half-life in dialysis patients is approximately 20 hours and the plasma AUC is increased by about 3-fold.
The AUC and Cmax in pediatric subjects are higher in proportion to their lower body weight, and half-life is reduced to 5.6 hours.
Indications And Clinical Uses: For the relief of symptoms associated with seasonal allergic rhinitis, perennial allergic rhinitis and chronic idiopathic urticaria; i.e., sneezing, rhinorrhea, postnasal discharge, tearing and redness of the eyes, pruritus and hives.
Contra-Indications: In those patients with a known hypersensitivity to it or to its parent compound, hydroxyzine.
Manufacturers’ Warnings In Clinical States: Pregnancy: No teratogenic effects were caused by oral doses as high as 60, 188 and 133 times the maximum clinically studied human dose in mice, rats and rabbits respectively. No effects on reproduction and fertility were observed at doses as high as 40 and 10 times the maximum recommended human dose in male and female mice respectively. An oral dose 60 times the maximum clinically studied human dose in female mice did not affect parturition or lactation. Although the animal studies are not indicative of any adverse effects during pregnancy at clinically relevant doses, such studies are not always predictive of a human response. There are no adequate, well-controlled studies of pregnant women. Until such data become available, cetirizine should not be used during pregnancy, unless advised otherwise by a physician.
Lactation: Studies in beagles indicate that approximately 3% of the dose is excreted in milk. The extent of excretion in human milk is unknown. Use of cetirizine in nursing mothers is not recommended, unless directed otherwise by a physician.
Children: Unless directed otherwise by a physician, cetirizine should not be administered to children under 12 years of age since its safety and effectiveness in this age group has not yet been established.
Occupational Hazards: Activities Requiring Mental Alertness: Studies using objective measurements have shown no effect of cetirizine on cognitive function, motor performance or sleep latency. However, in clinical trials the appearance of some CNS effects, particularly somnolence, have been observed. Due caution should be exercised when driving a car or operating potentially dangerous machinery.
Geriatrics: Cetirizine was well tolerated by patients aged 65 years and over. Clearance of cetirizine is reduced in proportion to creatine clearance. In patients whose creatinine clearance is reduced (i.e., those with moderate renal impairment), a starting dose of 5 mg/day is recommended (see Pharmacology, Pharmacokinetics).
Occasional instances of liver function test (transaminase) elevations have occurred during cetirizine therapy. This incidence was 1.6% in the short-term trials and 4.4% in the 6-month trials. These liver enzyme elevations, mainly ALT, were generally reversible. There was no evidence of jaundice or hepatitis, and the clinical significance is presently unknown. Consequently, cetirizine should be used with caution in patients with pre-existing liver disease. In patients with moderate hepatic impairment, a starting dose of 5 mg/day is recommended.
Asthmatics: Cetirizine has been safely administered to patients with mild to moderate asthma. Cetirizine did not cause exacerbation of asthma symptoms.
Drug Interactions: No clinically significant drug interactions have been found with theophylline, pseudoephedrine, cimetidine, erythromycin and ketoconazole. Epidemiologic data suggest that there also would not be interaction with other macrolide antibiotics or imidazole antifungals. In clinical trials, cetirizine has been safely administered with beta-agonists, NSAIDs, oral contraceptives, narcotic analgesics, corticosteroids, H2-antagonists, cephalosporins, penicillins, thyroid hormones and thiazide diuretics. Interaction studies with cetirizine and alcohol or diazepam indicate that cetirizine does not increase alcohol-induced or diazepam-induced impairment of motor and mental performance.
Adverse Reactions: In clinical development programs (domestic and international), cetirizine has been evaluated in more than 6 000 treated patients at daily doses ranging from 5 to 20 mg. The most common adverse reactions were headache and somnolence. The incidence of headache associated with cetirizine was not different from the placebo. The incidence of somnolence associated with cetirizine was dose-related and predominantly mild to moderate. The incidence of somnolence in fixed dose studies was 6% for the placebo, 11% at 5 mg and 13.7% at 10 mg. Dry mouth was reported by 5% of patients (vs 2.3% for the placebo). Fatigue was reported by 5.9% of patients (vs 2.6% for the placebo).
Most adverse reactions reported during cetirizine therapy were mild to moderate. The incidence of discontinuation due to adverse reactions in patients receiving cetirizine was not significantly different from the placebo (1% vs 0.6% respectively, in placebo-controlled trials). There was no difference by gender or by body weight with regard to the incidence of adverse reactions.
Occasional instances of transient, reversible hepatic transaminase elevations have occurred during cetirizine therapy without evidence of jaundice, hepatitis or other clinical findings.
The following events were observed infrequently (equal to or less than 1%), in 3 982 patients who received cetirizine in U.S. trials, including an open study of 6 months’ duration; a causal relationship with cetirizine administration has not been established.
Application Site: application site reaction, injection site inflammation.
Autonomic Nervous System: anorexia, urinary retention, flushing, saliva increased.
Cardiovascular: palpitation, tachycardia, hypertension, arrhythmia, cardiac failure.
Central and Peripheral Nervous Systems: paraesthesia, confusion, hyperkinesia, hypertonia, migraine, tremor, vertigo, leg cramps, ataxia, dysphonia, abnormal coordination, hyperaesthesia, hypoesthesia, myelitis, paralysis, ptosis, speech disorder, twitching, visual field defect.
Endocrine: thyroid disorder.
Gastrointestinal: increased appetite, dyspepsia, abdominal pain, diarrhea, flatulence, constipation, vomiting, ulcerative stomatitis, tongue disorder, aggravated teeth caries, stomatitis, tongue discoloration, tongue edema, gastritis, hemorrhage rectum, hemorrhoids, melena, abnormal hepatic function.
Genitourinary: polyuria, urinary tract infection, cystitis, dysuria, haematuria, abnormal urine.
Hearing and Vestibular: earache, tinnitus, deafness, ototoxicity.
Metabolic/Nutritional: thirst, edema, dehydration, diabetes mellitus.
Musculoskeletal: myalgia, arthralgia, bone disorder, arthrosis, tendon disorder, arthritis, muscle weakness.
Psychiatric: insomnia, nervousness, depression, emotional lability, impaired concentration, anxiety, depersonalization, paranoia, abnormal thinking, agitation, amnesia, decreased libido, euphoria.
Resistance Mechanism: impaired healing, herpes simplex, infection, fungal infection, viral infection.
Respiratory System: epistaxis, rhinitis, coughing, respiratory disorder, bronchospasm, dyspnea, upper respiratory tract infection, hyperventilation, sinusitis, increased sputum, bronchitis, pneumonia.
Reproductive: dysmenorrhea, menstrual disorder, female breast pain, intermenstrual bleeding, leukorrhea, menorrhagia, unintended pregnancy, vaginitis, testes disorder.
Skin: pruritus, rash, skin disorder, dry skin, urticaria, acne, dermatitis, rash erythematous, sweating increased, alopecia, angiodema, furunculosis, bullous eruption, eczema, hyperkeratosis, hypertrichosis, photosensitivity reaction, photosensitivity toxic reaction, rash maculo-papular, seborrhea, purpura.
Special Senses: taste perversion, taste loss, parosmia.
Vision: eye abnormality, abnormal vision, eye pain, conjunctivitis, xerophthalmia, glaucoma, ocular hemorrhage.
Body as a Whole: weight increase, back pain, malaise, pain, chest pain, fever, asthenia, generalized edema, periorbital edema, peripheral edema, rigor, leg edema, face edema, hot flushes, enlarged abdomen, allergic reaction, nasal polyp.
Weight gain was reported as an adverse event in 0.4% of cetirizine patients in placebo controlled trials. In an open study of 6 months’ duration, the mean weight gain was 2.8% after 20 weeks, with no further increase at 26 weeks.
Occasional instances of transient, reversible hepatic transaminase elevations have occurred during cetirizine therapy.
In foreign marketing experience the following additional rare, but potential severe adverse events have been reported: hemolytic anemia, thrombocytopenia, orofacial dyskinesia, severe hypotension, anaphylaxis, hepatitis, glomerulonephritis, stillbirth and cholestasis.
In a 6-week, placebo-controlled study of 186 patients with allergic rhinitis and mild to moderate asthma, cetirizine 10 mg daily improved rhinitis symptoms and did not alter pulmonary function. This study supports the safety of administering cetirizine to allergic rhinitis patients with mild to moderate asthma.
Symptoms And Treatment Of Overdose: Symptoms: Overdose has not been reported with cetirizine in North America. In foreign marketing experience, somnolence has been reported in cases of overdose up to 150 mg. If an acute overdose occurs, evacuation of the stomach should be considered during the first few hours afterwards. tag_Treatment
Treatment: Treatment should be symptomatic and supportive taking into account any concomitantly ingested medications. There is no known specific antidote to cetirizine. Cetirizine is not effectively removed by dialysis, and dialysis will be ineffective unless a dialyzable agent has been concomitantly ingested. The minimal lethal oral dose in rodents is at least 590 times the maximum clinically studied dose.
Dosage And Administration: Adults and Adolescents Over 12 Years: The recommended initial dose is 5 to 10 mg, depending on symptom severity, given as a single daily dose, with or without food. Most patients begin with a dose of 10 mg. The time of administration may be varied to suit individual patient needs.
Clinical studies to date support treatment for up to 6 months. Thus medical recommendation is advised for long-term use.
Geriatrics: In patients with moderate hepatic and/or renal impairment, a starting dose of 5 mg/day is recommended.
Availability And Storage: Each white (dye-free), film-coated, scored ovoid tablet contains: cetirizine HCl 10 mg. Nonmedicinal ingredients: cornstarch, hydroxypropyl methylcellulose, lactose, magnesium stearate, polyethylene glycol, povidone and titanium dioxide. Plastic bottles of 100 and 500. Packages (for OTC use) of 6, 12 and 18. Store at room temperature between 15 and 30Â°C.
ZYRTEC® UCB Pharma Cetirizine HCl Histamine H1-Receptor Antagonist