Acrivastine

Teratogenic Effects

No evidence of teratogenicity was seen in rats and rabbits given acrivastine 1000 and 400 mg/kg/day, respectively (5900 and 4720 mg/m²/day or 249 and 200 times the recommended human daily dose). No evidence of teratogenicity was seen in rats given a combination of acrivastine 30 mg/kg/day and pseudoephedrine 150 mg/kg/day (177 and 885 mg/m²/day or 8 and 5 times the recommended human daily dose, respectively). Similarly, no evidence of teratogenicity was observed in rabbits given acrivastine 20 mg/kg/day and pseudoephedrine 100 mg/kg/day (236 and 1180 mg/m²/day or 10 and 7 times the recommended human daily doses, respectively). There are, however, no adequate and well-controlled studies in pregnant women. Because animal teratology studies are not always predictive of human responses, acrivastine capsules should be used during pregnancy only if the potential benefit justifies the potential risks to the fetus.

Nonteratogenic Effects

In a perinatal-postnatal study in rats, acrivastine given alone at levels up to 500 mg/kg/day (2950 mg/m²/day or 124 times the recommended human daily dose) was associated with maternal and neonatal mortality at the maximum dose level. Neonatal survival was decreased in rats given a combination of acrivastine 20 mg/kg/day and pseudoephedrine 100 mg/ kg/day (118 and 590 mg/m²/day or 5 and 3 times the human dose, respectively).

It is not known whether acrivastine is excreted in human milk; pseudoephedrine is excreted in human milk. Acrivastine capsules should only be used in nursing mothers when the potential benefit justifies the potential risks to the nursing infant.

Carcinogenicity studies with the combination of acrivastine and pseudoephedrine have not been performed. Oral doses of acrivastine alone at levels up to 40 mg/kg/day (236 mg/m²/day or 10 times the recommended human daily dose) for 20 to 22 months in rats and up to 250 mg/kg/day (750 mg/m²/day or 32 times the recommended human daily dose) for 20 to 24 months in mice revealed no evidence of carcinogenic potential. No evidence of mutagenicity (with or without metabolic activation) was observed in the Ames Salmonella mutagenicity assay or in the L5178Y/tk+/- mouse lymphoma assay. In an in vitro cytogenetic study performed in cultured human lymphocytes, acrivastine induced structural chromosomal abnormalities in the absence of metabolic activation, but not in its presence. In an in vivo cytogenetic study in rats given single oral doses of acrivastine up to 1000 mg/kg (5900 mg/m² or 249 times the recommended human daily dose) there were no structural chromosomal alterations.

Reproduction-fertility studies in rats given acrivastine alone at levels up to 200 mg/kg/day (1180 mg/m ²/day or 50 times the recommended human daily dose) had no effect on male or female fertility. Similarly, no effect on fertility was seen in male rats given acrivastine 20 mg/kg/day and pseudoephedrine 100 mg/kg/ day (118 and 590 mg/m ²/day or 5 and 3 times the recommended human daily doses, respectively) or in female rats given acrivastine 4 mg/kg/day and pseudoephedrine 20 mg/kg/day (23.6 and 118 mg/m²/day or 1 and 0.7 times the recommended human daily doses, respectively).

Information on the incidence of adverse events in clinical investigations conducted in the United States was obtained from 33 controlled and 15 uncontrolled clinical studies in which 2499 patients received acrivastine and 2631 patients received acrivastine plus pseudoephedrine hydrochloride for treatment periods ranging from one day to one year. The majority of patients in clinical trials were exposed to acrivastine or acrivastine plus pseudoephedrine for less than 90 days. Acrivastine dosage ranged from 3 to 96 mg/day; 1336 patients received dosages equal to or greater than acrivastine 24 mg/day. Acrivastine plus pseudoephedrine hydrochloride dosages ranged from acrivastine 8 to 48 mg/day plus pseudoephedrine hydrochloride 60 to 240 mg/day. A total of 2335 patients received three or four daily doses of acrivastine 8 mg plus pseudoephedrine hydrochloride 60 mg.

In controlled clinical trials, only 12 spontaneously elicited adverse events were reported with frequencies greater than 1% in the acrivastine plus pseudoephedrine hydrochloride treatment group (see Table 1).

TABLE 1. ADVERSE EVENTS REPORTED IN CLINICAL TRIALS^* (PERCENT OF PATIENTS REPORTING)^†:

* Includes all events regardless of casual relationship to treatment.
^† Includes all adverse events with a reported frequency of >1% for the acrivastine plus pseudoephedrine treatment group.
^‡ Acrivastine demonstrates a statistically higher frequency of events than placebo, p ≤0.05.

The nature and overall frequencies of adverse events from international clinical trials (35 studies involving approximately 1600 patients) were similar to the results obtained in the US studies.

Post-marketing clinical experience reports with acrivastine and acrivastine plus pseudoephedrine have included rare serious hypersensitivity reactions manifested by anaphylaxis, angioedema, bronchospasm, and erythema multiforme. No deaths associated with use of acrivastine or acrivastine plus pseudoephedrine have been reported.

Pseudoephedrine may cause ephedrine-like reactions such as tachycardia, palpitations, headache, dizziness, or nausea.

Serious skin reactions, including acute generalized exanthematous pustulosis (AGEP), have been reported with pseudoephedrine-containing products.