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DRUG INTERACTIONS
Carcinogenesis, Mutagenesis and Impairment of Fertility
There are no carcinogenicity trials of pseudoephedrine and cetirizine in combination.
Cetirizine
In a 2-year study in rats, cetirizine was not carcinogenic at dietary doses up to 20 mg/kg (approximately 15 times the maximum recommended daily dose in adults on a mg/m2 basis). In a 2-year study in mice, cetirizine caused an increased incidence of benign liver tumors in males at a dietary dose of 16 mg/kg (approximately 6 times the maximum recommended daily dose in adults on a mg/m2 basis). 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 dose in adults on a mg/m2 basis). The clinical significance of these findings during long-term use of ZYRTEC-D 12 HOUR Extended Release Tablets is not known.
Pseudoephedrine
Two-year studies in rats and mice conducted under the auspices of the National Toxicology Program (NTP) demonstrated no evidence of carcinogenic potential with ephedrine sulfate, a structurally related drug with pharmacological properties similar to pseudoephedrine, at dietary doses up to 10 and 27 mg/kg, respectively (approximately 1/3 and 1/2, respectively, the maximum recommended daily dose of pseudoephedrine in adults on a mg/m2 basis).
Cetirizine was not mutagenic in the Ames test or mouse lymphoma test and not clastogenic in the human lymphocyte assay or the in vivo rodent micronucleus test. Likewise, the combination of cetirizine and pseudoephedrine in a 1:24 ratio was not mutagenic or clastogenic in these tests. However, the Ames and mouse lymphoma assays did not strictly adhere to test standards.
In a reproductive toxicity study in rats, combination oral doses of cetirizine and pseudoephedrine up to 6/154 mg/kg (approximately 5 times the maximum recommended daily dose in adults on a mg/m2 basis) had no effect on fertility.
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OVERDOSAGE
Information regarding acute overdosage is limited to experience with cetirizine alone and the marketing history of pseudoephedrine hydrochloride.
Overdosage has been reported with cetirizine. In one adult patient who took 150 mg of cetirizine, the patient was somnolent but did not display any other clinical signs or abnormal blood chemistry or hematology results. In an 18-month-old pediatric patient who took an overdose of cetirizine (approximately 180 mg), restlessness and irritability were observed initially; this was followed by drowsiness. Should overdose occur, treatment should be symptomatic or 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 acute minimal lethal oral doses in mice and rats were 237 and 562 mg/kg, respectively (approximately 95 and 460 times the maximum recommended daily dose in adults on a mg/m2 basis). In rodents, the target of acute toxicity was the central nervous system, and the target of multiple-dose toxicity was the liver.
In large doses, sympathomimetics may give rise to giddiness, headache, nausea, vomiting, sweating, thirst, tachycardia, precordial pain, palpitations, difficulty in micturition, muscular weakness and tenseness, anxiety, restlessness, and insomnia. Many patients can present a toxic psychosis with delusions and hallucinations. Some may develop cardiac arrhythmias, circulatory collapse, convulsions, coma and respiratory failure.
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CONTRAINDICATIONS
ZYRTEC-D 12 HOUR Extended Release Tablets are contraindicated in patients with a known hypersensitivity to any of its ingredients or to hydroxyzine.
Due to its pseudoephedrine component, ZYRTEC-D 12 HOUR Extended Release Tablets are contraindicated in patients with narrow-angle glaucoma or urinary retention, and in patients receiving monoamine oxidase (MAO) inhibitor therapy or within fourteen (14) days of stopping such treatment (see PRECAUTIONS, Drug Interactions section). It is also contraindicated in patients with severe hypertension, or severe coronary artery disease, and in those who have shown hypersensitivity or idiosyncrasy to its components, to adrenergic agents, or to other drugs of similar chemical structures. Manifestations of patient idiosyncrasy to adrenergic agents include insomnia, dizziness, weakness, tremor, or arrhythmias.
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