Risk Factor: CM
Class: Anti-infectives/ Quinolones
Fetal Risk Summary
Enoxacin is an oral, synthetic, broad-spectrum antibacterial agent. As a fluoroquinolone, it is in the same class of agents as ciprofloxacin, levofloxacin, lomefloxacin, norfloxacin, ofloxacin, and sparfloxacin. Nalidixic acid is also a quinolone drug.
No effects on fertility were observed in female rats at a dose of 1000 mg/kg, approximately 13 times the maximum human clinical daily dose on a mg/m2 basis (1). Decreased spermatogenesis and subsequent impaired fertility were observed in male rats at this dose. No evidence of teratogenicity was observed in either mice or rats following administration of oral enoxacin (dose not specified) (1). In pregnant rabbits, however, an intravenous infusion of 1050 mg/kg enoxacin produced maternal and fetal toxicity, the latter at the highest dose tested (maximum recommended human dose is 800 mg/day, or 16 mg/kg for a 50-kg individual). Fetal toxicity consisted of increased post-implantation loss and stunted fetuses and, in the presence of maternal and fetal toxicity, a significant increase in the incidence of congenital malformations (type not specified). As with other quinolones, multiple doses of enoxacin produced permanent lesions and erosion of cartilage in weight-bearing joints leading to lameness in immature rats and dogs (1).
It is not known if enoxacin crosses the placenta to the human fetus, but the molecular weight (about 320) is low enough that transfer to the fetus should be expected. Only one report describing the use of the antibiotic in human gestation has been located.
In a prospective follow-up study conducted by the European Network of Teratology Information Services (ENTIS), data on 549 pregnancies exposed to fluoroquinolones (1 to enoxacin) were described in a 1996 Reference (see Ciprofloxacin for full details of this study) (2). Data on another 116 prospective and 25 retrospective pregnancy exposures to the antibacterials were also included. Of the 666 cases with known outcome, 32 (4.8%) of the embryos, fetuses, or newborns had congenital malformations. None of the outcomes with congenital anomalies had been exposed to enoxacin. Based on previous epidemiologic data, the authors concluded that the 4.8% frequency of malformations did not exceed the published background rate (2). Finally, data on 25 retrospective pregnancies that had been exposed in utero to fluoroquinolones were described, but no specific patterns of major congenital malformations were detected.
The authors of the above study concluded that pregnancy exposure to quinolones was not an indication for termination, but that this class of antibacterials should still be considered contraindicated in pregnant women because there were several, safer alternatives that could be used in pregnancy (2). Because of their own and previously published findings, they further recommended that the focus of future studies should be on malformations involving the abdominal wall and urogenital system, and limb reduction defects. Moreover, this study did not address the issue of cartilage damage from quinolone exposure and the authors recognized the need for follow-up studies of this potential toxicity in children exposed in utero.
In summary, although only one report describing the use of enoxacin during human gestation has been located, the available evidence for other members of this class indicates that a causal relationship with birth defects cannot be excluded (see also Ciprofloxacin, Norfloxacin, or Ofloxacin). Because of this and the available animal data, the use of enoxacin during pregnancy, especially during the 1st trimester, should be considered contraindicated. A 1993 review on the safety of fluoroquinolones concluded that these antibacterials should be avoided during pregnancy because of the difficulty in extrapolating animal mutagenicity results to humans and because interpretation of this toxicity is still controversial (3). The authors of this review were not convinced that fluoroquinolone-induced fetal cartilage damage and subsequent arthropathies were a major concern, even though this effect had been demonstrated in several animal species after administration to both pregnant and immature animals and in occasional human case reports involving children (3). Others have also concluded that fluoroquinolones should be considered contraindicated in pregnancy, because safer alternatives are usually available (2).
Breast Feeding Summary
The administration of enoxacin during breast feeding is not recommended due to the potential for arthropathy and other serious toxicity in the nursing infant (1). Phototoxicity has been observed with quinolones, including enoxacin, when exposure to excessive sunlight (i.e., UV light) has occurred (1). Well-differentiated squamous cell carcinomas of the skin has been produced in mice who were exposed chronically to some quinolones and periodic UV light (e.g., see Lomefloxacin), but studies to evaluate the carcinogenicity of enoxacin in this manner have not been conducted.
No reports describing the use of enoxacin in human lactation or measuring the amount of the antibacterial in breast milk have been located. The antibacterial is excreted into the milk of lactating rats (1). Other quinolones are excreted into human milk (see Ciprofloxacin and Nalidixic Acid) and, because of its relatively low molecular weight (about 320), the passage of enoxacin into milk should be expected. Due to the potential for toxicity, the drug should be avoided during breast feeding.
- Product information. Penetrex. Rhne-Poulenc Rorer, 1997.
- Schaefer C, Amoura-Elefant E, Vial T, Ornoy A, Garbis H, Robert E, Rodriguez-Pinilla E, Pexieder T, Prapas N, Merlob P. Pregnancy outcome after prenatal quinolone exposure. Evaluation of a case registry of the European Network of Teratology Information Services (ENTIS). Eur J Obstet Gynecol Reprod Bio 1996;69:839.
- Norrby SR, Lietman PS. Safety and tolerability of fluoroquinolones. Drugs 1993;45(Suppl 3):5964.