Astemizole
Name: ASTEMIZOLE
Class: Antihistamine
Risk Factor: CM
Fetal Risk Summary
Breast Feeing Summary
References
Fetal Risk Summary
Astemizole is a long-acting, nonsedating antihistamine that is used for the relief of symptoms caused by seasonal allergic rhinitis and chronic idiopathic urticaria. The lack of sedative action is a result of the drug's inability to reach H1-receptors in the mother's brain, thus occupying only peripheral H1-receptors (1). It is not known, however, if drug transfer is also blocked by the fetal blood-brain barrier. Because of the very long terminal half-life after chronic administration, about 19 days for the pharmacologically active fraction of parent drug and hydroxylated metabolites, it could take up to 4 months after the last dose to completely eliminate the metabolites from the mother's body (1). Conception during this interval, therefore, could result in exposure of the embryo and fetus.
Astemizole was not teratogenic in rats and rabbits at doses of 200 times the recommended human dose (RHD), but maternal toxicity in rabbits was evident at this dose (1). Maternal toxicity and embryocidal effects were seen at 100 times the RHD in rats. Neither maternal toxicity nor embryo toxicity was observed in either species at 50 times the RHD (1). The lack of teratogenicity in rats and rabbits was also discussed in a 1986 letter from the manufacturer (2).
The long-term behavioral and anatomic effects in rat pups have been examined after exposure throughout gestation to a maternal dose (10 mg/kg/day) that produced neither adverse maternal body weight changes nor other maternal toxicity (3). In comparisons between astemizole-exposed pups and controls, no difference was found in the average number of pups alive at birth. No gross malformations or pups dead at birth were found in either group. The mean birth weight, however, was significantly less (p<0.05) in the exposed group than in controls and stayed significantly less throughout the 21-day lactation period. Compared with controls, two landmark and reflex development parameters, the appearance of pinna detachment and auditory startle reflex, were significantly (p<0.05) delayed in astemizole-exposed pups. Five other parameters, incisor eruption, eyes opening, vaginal opening, testes descent, and negative geotaxis, did not differ between the groups. In open field tests of locomotion, rearing frequencies, immobility duration, and defecation, the two groups were similar. When the locomotion test results were compared by sexes, however, exposed male pups were delayed compared with male controls, whereas exposed females were faster than their controls. Finally, prenatally exposed male rats exhibited significantly less (p<0.05) reproductive behavior than controls and had a significant reduction in testis wet weight. No differences in the sexual behavior tests were observed in the two groups of female rats. Although the exact cause of the above differences was not determined, the authors proposed that the mechanism may have been interference with the hormonal mechanism regulating central nervous system masculinization or a direct action on the pups during development (3).
No studies have been located that describe the placental transfer of astemizole in animals or humans. The molecular weight of the drug (about 459) is low enough that transfer to the fetus would normally be expected and the fetal effects noted above indicate that transfer did occur.
In a prospective, controlled, observational study, two teratogen information services compared the pregnancy outcomes of 114 women who took astemizole during the 1st trimester of pregnancy to the outcomes of 114 control women, matched for age, smoking, and alcohol use, who had consulted one of the services after exposure to nonteratogen agents (4). The mean dose ingested (10 mg/day) was taken by 76 women up to 16 weeks' gestation, 38 women took it for longer periods. A final follow-up interview was conducted at least 6 months after delivery. No statistically significant differences were recorded between the groups in prepregnancy weight, weight gain during pregnancy, mode of delivery, gestational age at birth, or number of live births, spontaneous abortions, elective abortions, or stillbirths. Two major malformations were observed in each group (1.9% in each). In the astemizole-exposed group, one case of hypospadias and one of spina bifida occulta were observed. Both infants had been exposed throughout the 1st trimester. In the control group, one infant had a ventricular septal defect and the other had ocular myopathy. The authors concluded that their results suggested that the drug could be used safely during pregnancy (4).
A 1998 letter, however, challenged the above conclusion because the letter's authors calculated the upper value of the 95% confidence interval of the drug's relative risk to be 7.5 (5). They claimed, therefore, that the sample size was too small to detect an increased incidence of birth defects.
A brief 1997 review on the use of H1-receptor blocking antihistamines concluded that first generation antihistamines were preferred over second generation agents (6). In particular, the authors recommended chlorpheniramine as the preferred oral agent and diphenhydramine as the preferred parenteral antihistamine. They also concluded that if a second-generation drug (e.g., astemizole) is required, exposure during organogenesis should be avoided except when the expected benefit is large (6). For pregnant patients with daily symptoms of allergic rhinitis, they recommended intranasal cromolyn or, if that is not successful, then intranasal beclomethasone supplemented, if necessary, with antihistamines. Antihistamines were recommended for pregnant patients with intermittent symptoms (6).
In summary, limited data on the use of astemizole during animal and human pregnancy, including the 1st trimester, do not support a major teratogenic risk for this antihistamine. Although H1-receptor occupying antihistamines, in general, are considered relatively safe during pregnancy (7), the number of human exposures to astemizole are too small to exclude such a risk completely. Moreover, the subtle behavioral and anatomic changes noted in one animal study are of concern and need to be addressed in future human research of offspring exposed in utero to this agent. Until more data are available in these and related areas, the safest course is to avoid the use of astemizole during the period of organogenesis.
Breast Feeing Summary No reports describing the use of astemizole during human lactation or measuring the amount, if any, of the drug excreted into milk have been located. The molecular weight of astemizole (about 459) is low enough, however, that passage into breast milk should be expected. The effects of this potential exposure on a nursing infant are unknown.
References
- Product information. Hismanal. Janssen Pharmaceutica, 1998.
- Whyatt PL. Astemizole in pregnancy. Aust Fam Physician 1986;15:382, 384.
- Almeida RG, Massoco CO, Spinosa HS, Bernardi MM. Perinatal astemizole exposure in the rat throughout gestation: long-term behavioral and anatomic effects associated with reproduction. Comp Biochem Physiol 1996;114C:123–7.
- Pastuszak A, Schick B, D'Alimonte D, Donnenfeld A, Korean G. The safety of astemizole in pregnancy. J Allergy Clin Immunol 1996;98:748–50.
- Kelso JM, Schatz M. Astemizole use in pregnancy. J Allergy Clin Immunol 1998;101:144.
- Schatz M, Petitti D. Antihistamines and pregnancy. Ann Allergy Asthma Immunol 1997;78:157–9.
- Seto A, Einarson T, Koren G. Pregnancy outcome following first trimester exposure to antihistamines: meta-analysis. Am J Perinatol 1997;14:119–24.
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