Respiratory Drug (Corticosteroid)
PREGNANCY RECOMMENDATION: Compatible
BREASTFEEDING RECOMMENDATION: No Human Data—Probably Compatible
PREGNANCY SUMMARY
Four reports totaling 201 women have described the use of fluticasone during pregnancy. No increase in the rates of embryo, fetal, or newborn toxicity were observed. Although the animal data suggest high risk, SC doses were used, resulting in much higher systemic concentrations than those obtained in humans after inhalation. Because of the initial absence of human pregnancy experience, two reviews concluded that either beclomethasone or budesonide were the inhaled corticosteroids of choice if such therapy is initiated in pregnancy (1,2). However, the new data suggest that if a nonpregnant woman has shown a good response to fluticasone, or if the agent is indicated in a pregnant woman, the drug is compatible with pregnancy.
FETAL RISK SUMMARY
Fluticasone, a synthetic trifluorinated glucocorticoid, is indicated for the maintenance treatment of asthma as a prophylactic therapy. In human lung preparations, the affinity of fluticasone for the glucocorticoid receptor is almost twice that of the active metabolite of betamethasone, and more than 3 and 18 times greater that of budesonide and dexamethasone, respectively. Although the oral bioavailability of fluticasone is negligible (<1%), the systemic bioavailability after inhalation is high (about 30% of the dose). Peak plasma levels after an 880-mcg inhaled dose were in the range of 0.1–1.0 ng/mL. The only metabolite that has been identified in humans is relativity inactive (about 2000 times less affinity than the parent drug for the glucocorticoid receptor). Plasma protein binding of the parent compound is about 91%. Excretion is mostly in the feces with a terminal plasma elimination half-life of about 7.8 hours (3).
Reproduction studies have been conducted with SC doses in mice, rats, and rabbits. In mice and rats, SC doses approximately 0.1 and 0.5 times the maximum human daily inhalation dose based on BSA (MRHID), respectively, revealed embryonic growth restriction, omphalocele, cleft palate, and retarded cranial ossification. This toxicity was considered characteristic of potent glucocorticoid compounds as rodents may be more prone to teratogenic effects from these agents than humans (3). In male and female rats, no evidence of impaired fertility was observed with SC doses up to about 0.25 times the MRHID, but prostate weight was significantly reduced. Fluticasone was not tumorigenic in long-term studies in mice and rats, nor was it mutagenic or clastogenic in various in vitro assays. In pregnant rabbits, SC doses approximately 0.04 times the MRHID were associated with fetal weight reduction and cleft palate. Oral doses approximately 3 times the MRHID did not cause maternal toxicity or increase the incidence of external, visceral, or skeletal fetal defects. After oral doses in rats and rabbits that were about 0.5 and 3 times the MRHID, respectively, less than 0.008% of the dose crossed the placenta. However, consistent with its poor oral absorption, fluticasone was not detected in the maternal rabbit plasma (3). Although not stated, poor absorption in the rat probably also occurred.
It is not known if fluticasone can cross the human placenta. As noted above, the systemic concentrations of fluticasone after inhalation are very low. Moreover, the placenta is a rich source of enzymes that can metabolize corticosteroids (e.g., see Betamethasone, Dexamethasone, Hydrocortisone, and Prednisolone). These factors suggest that clinically significant exposure of the embryo or fetus is unlikely.
A 2004 study examined the effect of inhaled corticosteroids on low birth weight, preterm births, and congenital malformations in pregnant asthmatic patients (4). The inhaled steroids and the number of patients were beclomethasone (N = 277), fluticasone (N = 132), triamcinolone (N = 81), budesonide (N = 43), and flunisolide (N = 25). Compared with the general population, the study found no increased incidence of small-for-gestational-age infants (less than 10th percentile for gestational age), low birth weight (<2500 g), preterm births, and congenital malformations (4).
Three reports described the use of fluticasone nasal spray in 69 pregnant women, sometimes compared with placebo controls (5–7). No effects on fetal growth or pregnancy outcomes were observed in these patients. Although most synthetic corticosteroids are partially metabolized by the placental enzymes, budesonide and fluticasone were not (6).
A 2006 meta-analysis on the use of inhaled corticosteroids during pregnancy was published in 2006 (8). The analysis included five agents: beclomethasone, budesonide, flunisolide, fluticasone, and triamcinolone. The results showed that these agents do not increase the risk of major congenital defects, preterm delivery, low birth weight, and pregnancy-induced hypertension. Thus, they could be used during pregnancy (8).
BREASTFEEDING SUMMARY
No reports describing the use of fluticasone during human lactation have been located. Because of the low systemic concentrations obtained with fluticasone inhalation, and the drug’s poor oral bioavailability, it is doubtful if clinically significant amounts would be ingested by a nursing infant.
References
1.Tan KS, Thomson NC. Asthma in pregnancy. Am J Med 2000;109:727–33.
2.Joint Committee of the American College of Obstetrics and Gynecologists (ACOG) and the American College of Allergy, Asthma and Immunology (ACAAI). Position statement. The use of newer asthma and allergy medications during pregnancy. Ann Allergy Asthma Immunol 2000;84:475–80.
3.Product information. Flovent. GlaxoSmithKline, 2005.
4.Namazy J, Schatz M, Long L, Lipkowitz M, Lillie M, Voss M, Deitz RJ, Petitti D. Use of inhaled steroids by pregnant asthmatic women does not reduce intrauterine growth. J Allergy Clin Immunol 2004;113:427–32.
5.Ellegard EK, Hellgren M, Karlsson NG. Fluticasone propionate aqueous nasal spray in pregnancy rhinitis. Clin Otolaryngol 2001;26:394–400.
6.Murphy VE, Fittock RJ, Zarzycki PK, Delahunty MM, Smith R, Clifton VL. Metabolism of synthetic steroids by the human placenta. Placenta 2007;28:39–46.
7.Choi JS, Han JY, Kim MY, Velazquez-Armenta EY, Nava-Ocampo AA. Pregnancy outcomes in women using inhaled fluticasone during pregnancy: a case series. Allergol Immunopathol (Madr) 2007;35:239–42.
8.Rahimi R, Nikfar S, Abdollahi M. Meta-analysis finds use of inhaled corticosteroids during pregnancy safe: a systematic meta-analysis review. Hum Exp Toxicol 2006;25:447–52.