CLARITHROMYCIN

Fetal Risk Summary

Clarithromycin, a semisynthetic antibiotic structurally related to erythromycin, belongs to the same macrolide class of anti-infectives as azithromycin, dirithromycin, erythromycin, and troleandomycin (the triacetyl ester of oleandomycin).

The effects of clarithromycin on fertility and reproduction in rats, mice, rabbits, and monkeys have been reported by the manufacturer (1). Doses up to 160 mg/kg/day (1.3 times the recommended maximum human dose based on mg/m2 [MRHD]; serum levels approximately 2 times the levels in humans) in male and female rats produced no adverse effects on the estrous cycle, fertility, parturition, or fetal outcome. No teratogenic effects were observed in four studies involving one rat strain using oral and IV doses up to 160 mg/kg/day, but a low incidence of cardiovascular anomalies were seen in two studies with a second rat strain administered 150 mg/kg/day orally. A variable incidence of cleft palate occurred in mice given oral doses of 500 to 1000 mg/kg/day (about 2 to 4 times the MRHD).

In rabbits, IV doses 17 times less than the MRHD resulted in fetal death, but teratogenic effects were not observed with various oral or IV doses (1). Embryonic loss attributed to maternal toxicity occurred in monkeys administered oral doses of 150 mg/kg/day (2.4 times the MRHD; serum levels 3 times the levels in humans). In monkeys, an oral dose of 70 mg/kg/day, approximately equal to the MRHD, produced serum levels about twice those obtained in humans and caused fetal growth retardation.

At a 1996 meeting, a teratogen information service (TIS) reported the outcomes of 34 exposures to clarithromycin during pregnancy (2). All of the exposures occurred during the 1st and early 2nd trimesters for the treatment of upper respiratory infections. Among the 29 known pregnancy outcomes (5 were pending), there were 8 (28%) abortions (4 spontaneous/4 voluntary), 20 (69%) normal newborns, and 1 (3%) infant with a 0.5 cm brown mark on the temple. One of the normal newborns, delivered at 26 weeks, died from complications of prematurity. Although follow-up of the remaining newborns had not been long enough to completely exclude the presence of congenital malformations, these outcomes do not appear to be different from those expected in a nonexposed population.

Case reports of clarithromycin and congenital anomalies available to the FDA through June 1996 were limited to six diverse birth defects: cystic head, pregnancy terminated; craniofacial anomalies, absent clavicles, bilateral hip deformities, and underdeveloped left heart; spina bifida; cleft lip; pulmonary hypoplasia, anomalous infradiaphragmatic venous return; and CHARGE syndrome (F. Rosa, personal communication, FDA, 1996). By definition, infants having CHARGE association or syndrome must have two or more of the following: coloboma of the eye or eye defects, heart disease, choanal atresia, retarded growth and development with or without CNS anomalies, genital hypoplasia, and ear anomalies with or without deafness (3). The diversity of the malformations lessens the probability of an association with clarithromycin and any or all of these outcomes may have occurred by chance.

A 1998 prospective controlled multicenter study compared the outcomes of 157 pregnancies exposed to clarithromycin to an equal number of matched controls (4). All of the women had called a TIS. The most common indications for use of the antibiotic were respiratory infections. Of the subjects, 122 (78%) were exposed during the 1st trimester. The outcomes of subjects and controls were: spontaneous abortions (22 vs. 11, p=0.04), elective abortions (11 vs. 3, p=0.04), live births (123 vs. 143, p=0.003), stillbirths (1 vs. 0, ns), major malformations (3 vs. 2, ns), and minor malformations (7 vs. 7, ns). The major anomalies (exposure occurred in the 3rd trimester in one case) in the study group were hydrocephalus, Turner syndrome, and stenosis uteropelvic junction and cranial synostosis. The minor malformations were a large birth mark, a reflux valve problem, an enlarged right ventricle (brain), a minor ventricular septal defect, undescended testes, a blocked tear ducts defect, and excess breast tissue on the right. The types of malformations in controls were comparable, with no pattern of defects apparent in either group. Although the increased number of spontaneous abortions in exposed women was within the expected background rate and may have been effected by confounding factors, the investigators concluded that it warranted further study (4).

Three pregnant women with documented Helicobacter pylori infections, persistent nausea and vomiting, and epigastric pain were treated in the 2nd trimester with a 2-week course of clarithromycin combined with amoxicillin and either famotidine, omeprazole, or ranitidine (5). The therapy was effective in eliminating the conditions. No adverse effects on the pregnancy outcomes were noted.

Breast Feeding Summary

No reports describing the use of this macrolide antibiotic during lactation have been located. Because other antibiotics in this class are excreted into milk (e.g., see Erythromycin), the passage of clarithromycin into milk should be expected. Clarithromycin is excreted in the milk of rats with milk concentrations higher than those measured in the plasma (1). Exposure of the pups to the antibiotic via milk for 3 weeks produced no adverse effects. Based on experience with other antibiotics, including erythromycin, the risk to a nursing infant from clarithromycin in breast milk is probably minimal, but, because this is a new drug, caution should be exercised until the effects of this exposure, if any, have been studied.

References

1. Product information. Biaxin. Abbott Laboratories, 1996.
2. Schick B, Hom M, Librizzi R, Donnenfeld A. Pregnancy outcome following exposure to clarithromycin (abstract). Abstracts of the Ninth International Conference of the Organization of Teratology Information Services, May 2–4, 1996, Salt Lake City, Utah. Reprod Toxicol 1996;10:162.
3. Escobar LF, Weaver DD. Charge Association. In Buyse ML, ed. Birth Defects Encyclopedia. Volume 1. Dover,MA:Center for Birth Defects Information Services, 1990:308–9.
4. Einarson A, Phillips E, Mawji F, D'Alimonte D, Schick B, Addis A, Mastroiacova P, Mazzone T, Matsui D, Koren G. A prospective controlled multicentre study of clarithromycin in pregnancy. Am J Perinatol 1998;15:523–5.
5. Jacoby EB, Porter KB. Helicobacter pylori infection and persistent hyperemesis gravidarum. Am J Perinatol 1999;16:85–8.