Mutagenicity
 

Lomefloxacin —One study lasting up to 52 weeks showed that 92% of hairless (Skh-1) mice that were exposed to UVA light for 3.5 hours, five times every two weeks, and that had received lomefloxacin concurrently developed skin tumors within 16 weeks. These tumors were well-differentiated squamous cell carcinomas of the skin that were nonmetastatic and endophytic in character. Two thirds of these squamous cell carcinomas contained large keratinous inclusion masses and were thought to arise from the vestigial hair follicles in these hairless animals.
Lomefloxacin package insert (Maxaquin, Unimed—US), Rev 8/97, Rec 1/98.

Ciprofloxacin — In vitro mutagenicity studies have showning positive results were obtained in the mouse lymphoma cell forward mutation assay and the rat hepatocyte DNA repair assay.
Ciprofloxacin package insert for oral administration (Cipro, Bayer—US), Rev 12/98, Rec 2/99.

Enoxacin —Minimal, dose-related, statistically significant increase in micronuclei at high doses of enoxacin in mice.
Enoxacin package insert (Penetrex, Rhone-Poulenc Rorer—US), Rev 7/98, Rec 2/99.

Gatifloxacin —Gatifloxacin was positive in in vitro gene-mutation assays in Chinese hamster V-79 cells and in vivo cytogenetics assays in Chinese hamster CHL/IU cells.
Product Information: Tequin™ (gatifloxacin) tablets and intravenous solution, Bristol-Myers Squibb, Princeton, NJ. rev 12/99, reviewed 2/2000.

Levofloxacin —Positive in the in vitro chromosomal aberration (CHL cell line) and sister chromatid exchange (CHL/IU cell line) assays.
Levofloxacin package insert (Levaquin, Ortho—US), Rev 8/98, Rec 2/99.

Lomefloxacin —One in vitro mutagenicity test (CHO/HGPRT assay) was weakly positive at concentrations of 226 mcg per mL (mcg/mL) and higher.
Lomefloxacin package insert (Maxaquin, Unimed—US), Rev 8/97, Rec 1/98.

Moxifloxacin —Moxifloxacin was clastogenic in the V79 chromosome aberration.
Product Information: Avelox™ (moxifloxacin), Bayer Pharmaceutical, West Haven, CT. rev. 1/2000, reviewed 2/2000.

Ofloxacin —Mutagenic in the unscheduled DNA repair test using rat hepatocytes and in the mouse lymphoma assay.
Ofloxacin package insert (Floxin, Ortho—US), Rev 8/98, Rec 2/99.

Sparfloxacin —Mutagenic in S. typhimurium TA102, and it induced DNA repair in E. coli . Sparfloxacin induced chromosomal aberrations in Chinese hamster lung cells in vitro at cytotoxic concentrations.
Sparfloxacin package insert (Zagam—Bertek, US), Rev 11/96, Rec 2/99.

 

Pregnancy/Reproduction
Fertility—

Ciprofloxacin: Adequate and well-controlled studies in humans have not been done.

Enoxacin : Decreased spermatogenesis and subsequent impaired fertility were noted in male rats given oral doses of 1000 mg/kg. {16}

Moxifloxacin: At 500 mg/kg, it had slight effects on sperm morphology (head-tail separation) in male rats and on the estrous cycle in female rats. {155}
 

Pregnancy—

For all fluoroquinolones: Adequate and well-controlled studies in humans have not been done.

Ciprofloxacin crosses the placenta {119} .
Studies in rabbits given oral doses of 30 and 100 mg/kg have shown that ciprofloxacin causes gastrointestinal disturbances, resulting in maternal weight loss and an increased incidence of abortion. FDA Pregnancy Category C {04} .

Enoxacin
Intravenous infusion of enoxacin into pregnant rabbits at doses of 10 to 50 mg/kg caused dose-related maternal toxicity (venous irritation, weight loss, and reduced food intake). At 50 mg/kg, there were increased incidences of postimplantation loss and stunted growth of fetuses. The incidence of fetal malformations also was significantly increased at this dose in the presence of overt maternal and fetal toxicity.
FDA Pregnancy Category C

Gatifloxacin
Skeletal malformations were observed in rats at an oral dose of 200 mg/kg/day or intravenous dose of 60 mg/kg/day during organogenesis. Fetotoxicity was seen in rat fetuses at oral doses ³ 150 mg/kg or intravenous doses ³ 30 mg/kg daily during organogenesis, and in rats during late pregnancy and throughout lactation at oral doses of 200 mg/kg.
FDA Pregnancy Category C

Levofloxacin
Doses equivalent to 81 and 26 times the MRHD of levofloxacin (based on body weight and body surface area, respectively) caused decreased fetal body weight and increased fetal mortality in rats when administered orally at doses of 810 mg/kg (8910 mg/m 2 ) per day
FDA Pregnancy Category C {17} .

Lomefloxacin
An increased incidence of fetal loss in monkeys has been observed at approximately 6 to 12 times the recommended human dose on a mg/kg basis. In rabbits, maternal toxicity and associated fetal toxicity, decreased placental weight, and variations of the coccygeal vertebrae occurred at doses two times the recommended human dose on a mg/m 2 basis. {03}
FDA Pregnancy Category C {03} .

Moxifloxacin
Fetotoxicity such as decreased fetal body weights and slightly delayed fetal skeletal development were observed. There was also an increase in the incidence of rib and vertebral malformations. There was no evidence of teratogenicity when pregnant Cynomolgus monkeys were given oral doses up to 100 mg/kg/day (2.5 times the MRHD based on systemic exposure). There was an increase in incidence of smaller fetuses. At dose of 500 mg/kg/day in rats, slight increase in duration of pregnancy and prenatal loss, reduced pup birth weight, decreased neonatal survival, and treatment-related maternal mortality were observed.
FDA Pregnancy Category C

Norfloxacin
Studies in monkeys given doses of 10 times the MRHD (800 mg daily) have shown that norfloxacin causes embryonic loss. Peak plasma concentrations were two to three times those seen in humans. Studies in cynomolgus monkeys given doses of 150 mg/kg per day or more have shown that norfloxacin is embryocidal and causes slight maternal toxicity (vomiting and anorexia) as well.
FDA Pregnancy Category C {09} .

Ofloxacin
Ofloxacin crosses the placenta.
In one small study, umbilical cord serum concentrations reached 80 to 90% of maternal serum concentrations after mothers received 200-mg doses. Ofloxacin was also detected in the amniotic fluid from more than 50% of the mothers {102} . Another small study found that ofloxacin concentrated in the amniotic fluid, reaching up to 35 to 257% of the simultaneous maternal serum concentration {119} .
Doses equivalent to 50 and 10 times the MRHD were fetotoxic in rats (decreased fetal body weight) and rabbits (increased fetal mortality), respectively. Rats given 810 mg/kg per day, greater than 10 times the MRHD, were reported to produce offspring with minor skeletal variations. {98}
FDA Pregnancy Category C {98} .

Sparfloxacin
Oral doses of 6.2, 4.4, and 2.6 times the MRHD (on a mg/m 2 basis), respectively, sparfloxacin produced clear evidence of maternal toxicity in rabbits and in monkeys, and slight evidence of maternal toxicity in rats. When administered to pregnant rats at clearly defined maternally toxic doses, sparfloxacin induced a dose-dependent increase in the incidence of ventricular septal defects in fetuses. Among the three species tested, this effect was specific to the rat. {52}
FDA Pregnancy Category C {52} .

 

Breast-feeding

Ciprofloxacin, ofloxacin, and sparfloxacin are known to be distributed into human breast milk {04} {52} {98} . The concentration of ofloxacin in breast milk is similar to that found in plasma {98} {102} . One small study found that ofloxacin was highly concentrated in breast milk, reaching 98% of the simultaneous maternal serum level within 2 hours of administration {119} . It is not known whether enoxacin, gatifloxacin, levofloxacin, lomefloxacin, moxifloxacin, or norfloxacin is distributed into breast milk. However, based on data for ofloxacin, it is expected that levofloxacin is distributed into breast milk {17} {155} {157} . Norfloxacin was not detected in breast milk following its administration in low (200-mg) doses to nursing mothers. However, other quinolone derivatives are distributed into human breast milk {03} {09} {16} . Moxifloxacin is distributed in the breast milk of lactating rats. {164}