Antihistamine
PREGNANCY RECOMMENDATION: No Human Data—Animal Data Suggest Low Risk
BREASTFEEDING RECOMMENDATION: No Human Data—Probably Compatible
PREGNANCY SUMMARY
No reports describing the use of azelastine in human pregnancy have been located. The animal data suggest that the risk to the embryo–fetus is low. Moreover, the systemic bioavailability of the antihistamine after intranasal administration is only 40% and it is much lower after ocular administration. Nevertheless, the complete absence of human pregnancy experience prevents a full assessment of the risk. A 2000 review of the use of newer asthma and allergy medications in pregnancy stated that, based on the animal studies, there were better choices available than azelastine (1).
FETAL RISK SUMMARY
The antihistamine azelastine is formulated for intranasal and ophthalmic administration. It is a phthalazinone derivative that has histamine H1-receptor antagonist activity. Azelastine nasal spray is indicated for the treatment of the symptoms of seasonal allergic rhinitis such as rhinorrhea, sneezing, and nasal pruritus and for the treatment of the symptoms of vasomotor rhinitis, such as rhinorrhea, nasal congestion, and postnasal drip (2). The ophthalmic preparation is indicated for the treatment of itching of the eye associated with allergic conjunctivitis (3).
The systemic bioavailability, after nasal administration, is 40% with peak plasma concentrations obtained in 2–3 hours (2). In contrast, very small amounts are absorbed after ophthalmic administration (3). The plasma concentrations of the major active metabolite desmethylazelastine range from 20% to 50% of the parent drug concentrations (2). The elimination half-lives of azelastine and the active metabolite are 22 and 54 hours, respectively.
Reproduction studies have been conducted in mice, rats, and rabbits. In pregnant mice, an oral dose about 280 times the maximum recommended daily intranasal dose in adults based on BSA (MRDID) caused embryo–fetal death, malformations (cleft palate; short or absent tail; fused, absent, or branched ribs), delayed ossification, and decreased fetal weight. However, the dose also was maternally toxic (decreased weight). Neither maternal nor fetal toxicity was noted at a dose 10 times the MRDID (2). In rats, a dose about 240 times the MRDID was not maternally toxic but did cause fetal malformations (oligo- and brachydactylia), and delayed and skeletal variations. A maternal toxic dose (560 times the MRDID) resulted in embryo–fetal death and decreased fetal weight. A dose 25 times the MRDID caused no toxicity in the mother or fetus (2,4). In rabbits, doses greater than 500 times the MRDID caused severe maternal toxicity and resulted in abortions, delayed ossification, and reduced fetal weight. Neither maternal nor fetal adverse effects were observed with a dose 5 times the MRDID (2,4). In peri- and postnatal studies with rats, doses 25–240 times the MRDID were not associated with toxicity in the pups in terms of physical growth, reflexive behavior, activity, motor coordination, and learning and reproductive performance (4).
No carcinogenic effects in mice and rats were observed in 2-year studies at doses 100 and 240 times the MRDID, respectively. In addition, studies with azelastine for genotoxicity were also negative, as were fertility tests in rats at 240 times the MRDID (2).
It is not known if azelastine crosses the human placenta. The molecular weight (about 382 for the free base) and prolonged elimination half-life suggest that the drug could cross to the embryo and fetus. However, the low systemic concentrations of the parent drug and major active metabolite suggest that the amount available at the maternal:fetal interface will be clinically insignificant.
BREASTFEEDING SUMMARY
No reports describing the use of azelastine during human lactation have been located. The relatively low molecular weight (about 382 for the free base) and the prolonged elimination half-lives of the parent drug and major active metabolite suggest that the drugs will be excreted into breast milk. However, the systemic bioavailability after intranasal administration is only 40% and is much lower after ocular administration. Therefore, it is doubtful if clinically significant amounts will be excreted into milk.
References
1.Joint Committee of the American College of Obstetricians and Gynecologists (ACOG) and the American College of Allergy, Asthma and Immunology (ACAAI). The use of newer asthma and allergy medications during pregnancy. Ann Allergy Asthma Immunol 2000;84:475–80.
2.Product information. Astelin. MedPointe Pharmaceuticals, 2004.
3.Product information. Optivar. MedPointe Pharmaceuticals, 2004.
4.Suzuki Y, Okada F, Mikami T, Goto M, Hasegawa H, Chiba T. Teratology and reproduction studies of azelastine, a novel antiallergic agent, in rats and rabbits. Arzneimittelforschung 1981;31:1225–30.