Norfloxacin Risk Summary

Risk Factor: CM
Class: Anti-infectives / Quinolones

Fetal Risk Summary

Norfloxacin is an oral, synthetic, broad-spectrum antibacterial agent. As a fluoroquinolone, it is in the same class as ciprofloxacin, enoxacin, levofloxacin, lomefloxacin, ofloxacin, and sparfloxacin. Nalidixic acid is also a quinolone drug.

In rats, high doses of norfloxacin administered before and at various intervals during gestation, including during organogenesis, did not produce an increase in congenital abnormalities, adverse effects on fertility, fetotoxicity, or changes in postnatal function in the offspring (1,2). Embryo lethality, but not teratogenicity, was observed in rabbits given 100 mg/kg (1), and in cynomolgus monkeys given 200 or 300 mg/day (200 mg/kg/day) (3). In the monkeys, plasma concentrations (about 3 times human therapeutic levels) were high enough to produce maternal toxicity (3). In the second part of this study, the cause of the embryotoxicity was found to be directly related to a decrease in placental-derived progesterone production (4).

In reproductive studies reported by the manufacturer, no evidence of teratogenicity was found in mice, rats, rabbits, or monkeys at 650 times the maximum daily human dose on a mg/kg basis (MDHD) (5). Embryonic loss was observed in monkeys with doses 10 times the MHDA (peak plasma levels about 2 times those obtained in humans).

A 1991 Reference evaluated the toxic effects of norfloxacin on rat liver and kidney DNA in mothers and their fetuses (6). Single oral doses of the antibiotic, ranging from 1 to 8 mmol/kg (3192552 mg/kg), about 30 times the human dose, were administered to pregnant rats on the 17th day of gestation. No DNA damage was observed in the female rats at any dose, but at 4 and 8 mmol/kg, a statistically significant decrease in the percentage of double-stranded DNA (i.e., an increase in DNA damage) was observed in fetal tissues. Because a dose-response relationship with the DNA fragmentation was lacking, and because of the very high doses administered, the investigators concluded that the results did not indicate genotoxicity, but most likely a nonspecific consequence of fetal toxicity. Thus, the potential for mutagenic and carcinogenic risk in humans was probably nil (6).

The effects of norfloxacin on spermatogenesis and sperm abnormalities were studied using a mouse sperm morphology test following either a single or five consecutive daily doses of 2 and 4 mmol/kg (7). Norfloxacin stimulated spermatogenesis, presumably through a hormonal action, and may have had a mutagenic effect that resulted in an increase in abnormal sperm morphology. However, because a significant dose-response relationship for adverse morphology was not observed, the investigators could not conclude with certainty that the antibiotic induced abnormal sperm (7).

In humans, norfloxacin crosses the placenta, appearing in cord blood and in amniotic fluid (T.P. Dowling, personal communication, Merck & Co, Inc., 1987). Following a single oral 200-mg dose given to nine patients, cord blood and amniotic fluid levels varied from undetectable to 0.18 g/mL and undetectable to 0.19 g/mL, respectively. Cord blood levels were about one-half of maternal serum levels. In another 14 women administered a single 200-mg dose, the peak maternal serum, cord blood, and amniotic fluid levels were 1.1, 0.38, and 0.92 g/mL, respectively.

No congenital malformations were observed in the infants of 38 women who received either norfloxacin (N=28) or ciprofloxacin (N=10) during pregnancy (35 in the 1st trimester) (8). Most (N=35) received the drugs for the treatment of urinary tract infections. Matched to a control group, the fluoroquinolone-exposed pregnancies had a significantly higher rate of cesarean section for fetal distress and their infants were significantly heavier. No differences were found between the groups in infant development or in the musculoskeletal system.

A surveillance study on the use of fluoroquinolones during pregnancy was conducted by the Toronto Motherisk Program among members of the Organization of Teratology Information Services and briefly reported in 1995 (9). Pregnancy outcome data were available for 134 cases, of which 61 were exposed to norfloxacin, 68 to ciprofloxacin, and 5 to both drugs. Most (90%) were exposed during the first 13 weeks postconception. Fluoroquinolone-exposed pregnancies were compared with matched controls and there were no differences in live births (87% vs. 86%), terminations (3% vs. 5%), miscarriages (10% vs. 9%), abnormal outcomes (7% vs. 4%), cesarean section rate (12% vs. 22%), fetal distress (15% vs. 15%), and pregnancy weight gain (15 kg vs. 16 kg). The birth weights of exposed infants was a mean 162 g higher than those in the control group and their gestations were a mean 1 week longer.

In a prospective follow-up study conducted by the European Network of Teratology Information Services (ENTIS), data on 549 pregnancies exposed to fluoroquinolones (318 to norfloxacin) were described in a 1996 Reference (10). Data on another 116 prospective and 25 retrospective pregnancy exposures to the antibacterials were also included. From the 549 follow-up cases, 509 were treated during the 1st trimester, 22 after the 1st trimester, and in 18 cases the exposure occurred at an unknown gestational time. The live-born infants were delivered at a mean gestational age of 39.4 1.5 weeks and had a mean birth weight of 3302 495 g, length of 50.3 2.3 cm, and head circumference of 34.9 1.5 cm. Of the 549 pregnancies, there were 415 live-born infants (390 exposed during the 1st trimester), 356 of which were normal term deliveries (including 1 set of twins), 15 were premature, 6 were small for gestational age (intrauterine growth retardation [IUGR], <10th percentile), 20 had congenital anomalies (19 from mothers exposed during the 1st trimester; 4.9%), and 18 had postnatal disorders unrelated to either prematurity, low birth weight, or malformations (10). Of the remaining 135 pregnancies, there were 56 spontaneous abortions or fetal deaths (none late) (1 malformed fetus), and 79 elective abortions (4 malformed fetuses). A total of 116 (all involving ciprofloxacin) prospective cases were obtained from a manufacturer's registry (8). Among these, there were 91 live-born infants, 6 of whom had malformations. Of the remaining 25 pregnancies, 15 were terminated (no malformations reported), and 10 aborted spontaneously (1 embryo with acardia, no data available on a possible twin). Thus, of the 666 cases with known outcome, 32 (4.8%) of the embryos, fetuses, or newborns had congenital malformations. From previous epidemiologic data, the authors concluded that the 4.8% frequency of malformations did not exceed the background rate (10). Finally, 25 retrospective reports of infants with anomalies, who had been exposed in utero to fluoroquinolones, were analyzed, but no specific patterns of major congenital malformations were detected.

The defects observed in 12 infants followed up prospectively and in 16 infants reported retrospectively who were exposed to norfloxacin were (10): Source: Prospective ENTIS Trisomy 18, heart defect Diastasis recti, mild hypospadias Patient ductus arteriosus (term) Central nervous system calcification, cataract Urogenital malformation (no uterus and gonad) Fossa posterior hypoplasia Bilateral ureterovesical reflux, hydronephrosis Herniation of abdominal viscera, rudimentary umbilical cord, severekyphoscoliosis, absent diaphragma and pericardium, ectopia cordis, imperforated anus, ambiguous genitalia, urinary bladder not identifiable (pregnancy terminated) Anencephaly (pregnancy terminated) Trisomy 21 Unilateral cryptorchidism Macroglossia (2nd-trimester exposure) (pregnancy terminated) Source: Retrospective Reports 1st-trimester exposure: Abdominal and thoracic wall defects, lungs outside of thoracic cavity,pericardium visible (pregnancy terminated) Achondroplastic dwarfism, (pregnancy terminated) Renal and ureteral agenesis, pulmonary hypoplasia Supraumbilical hernia Intestinal cystic duplication Ventricular septal defect Penoscrotal hypospadias 2nd-trimester exposure: Dysplastic hips Hypertelorism, cryptorchism, small penis, short thorax, heart valves dysplasia Urachal abnormality 3rd-trimester exposure: Microretrognathia Two nevi, 4 2 and 2 2 cm Talipes valgus Hands and feet syndactyly Trisomy 21 Short limbs (possibly familial) 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 (10). 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. 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 on limb reduction defects.

In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 139 newborns had been exposed to norfloxacin, 79 during the 1st trimester (F. Rosa, personal communication, FDA, 1994). Five (6.3%) major birth defects were observed (three expected), one of which was a brain defect that occurred in an infant whose mother consumed the drug after the 1st trimester. Details of the remaining cases were not available, but none of the abnormalities was included in seven other categories of defects (cardiovascular defects, oral clefts, spina bifida, polydactyly, limb reduction defects, hypospadias, and eye defects) for which specific data were available.

A 1998 prospective multi-center study reported the pregnancy outcomes of 200 women exposed to fluoroquinolones compared to 200 matched controls (11). Subjects were pregnant women who had called one of four teratogen information services concerning their exposure to fluoroquinolones. The agents, number of subjects, and daily doses were ciprofloxacin (N=105; 5001000 mg), norfloxacin (N=93; 400800 mg), and ofloxacin (N=2; 200400 mg). The most common infections involved the urinary tract (69.4%) or the respiratory tract (24%). The fewer live births in the fluoroquinolone group (173 vs. 188, p=0.02) were attributable to the greater number of spontaneous abortions (18 vs. 10, p=0.17) and induced abortions (9 vs. 2, p=0.06). There were no differences between the groups in terms of premature birth, fetal distress, method of delivery, low birth weight (<2500 g), or birth weight. Among the live-born infants exposed during organogenesis, major malformations were observed in 3 infants of 133 subjects and 5 of 188 controls (p=0.54). The defects in subject infants were two cases of ventricular septal defect and one case of patent ductus arteriosus, whereas those in controls were two cases of ventricular septal defect, one case of atrial septal defect with pulmonic valve stenosis, one case of hypospadias, and one case of displaced hip. There were also no differences between the children of the groups in gross motor development milestone achievements (musculoskeletal functions: lifting, sitting, crawling, standing, or walking) as measured by the Denver Developmental Scale (11).

In summary, the use of norfloxacin during human gestation does not appear to associated with an increased risk of major congenital malformations. Although a number of birth defects have occurred in the offspring of women who had taken this drug during pregnancy, the lack of a pattern among the anomalies is reassuring. However, a causal relationship with some of the birth defects cannot be excluded. Because of this and the available animal data, the use of norfloxacin during pregnancy, especially during the 1st trimester, should be approached with caution. 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 (12). 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 (12). Others have also concluded that fluoroquinolones should be considered contraindicated in pregnancy, because safer alternatives are usually available (10).

Breast Feeding Summary

The administration of norfloxacin during breast feeding is not recommended because of the potential for arthropathy and other serious toxicity in the nursing infant (5). Phototoxicity has been observed with some members of the quinolone class of drugs when exposure to excessive sunlight (i.e., ultraviolet [UV] light) has occurred (5). Well-differentiated squamous cell carcinomas of the skin have 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 norfloxacin in this manner have not been conducted.

The manufacturer reports that the drug was not detected in milk following a single 200-mg oral dose administered to nursing mothers (5). However, this dose is one-fourth of the normal recommended daily dose and, thus, may not be indicative of excretion after normal use. Similarly, a 1991 review cited a study that the antibacterial was undetectable in milk, but no details on dosage were given (13).

In a study published in 1994, lactating ewes were administered a single IV dose of norfloxacin (25 mg/kg) during nursing (14). Milk concentrations of the antibacterial agent were up to 40 times higher than corresponding serum levels and therapeutic levels were measured in the serum of suckling lambs.

Although it is not known whether norfloxacin is excreted into human milk, the high concentrations of the drug found in the milk of ewes, the relatively low molecular weight (about 319), and the excretion of other quinolones (see Ciprofloxacin and Ofloxacin), are evidence that the passage of norfloxacin most likely occurs. Because of the potential for toxicity, the drug should be avoided during breast feeding.

References

1. Irikura T, Imada O, Suzuki H, Abe Y. Teratological study of 1-ethyl-6-fluoro-1, 4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxilic acid (AM-715). Kiso to Rinsho 1981;15:525163. As cited in Shepard TH. Catalog of Teratogenic Agents. 7th ed. Baltimore, MD: Johns Hopkins University Press, 1992:290.
2. Irikura T, Suzuki H, Sugimoto T. Reproductive studies of AM-715. Chemotherapy 1981:29:88694, 895914, 91531. As cited in Shepard TH. Catalog of Teratogenic Agents. 7th ed. Baltimore, MD: Johns Hopkins University Press, 1992:290.
3. Cukierski MA, Prahalada S, Zacchei AG, Peter CP, Rodgers JD, Hess DL, Cukierski MJ, Tarantal AF, Nyland T, Robertson RT, Hendrickx AG. Embryotoxicity studies of norfloxacin in cynomolgus monkeys. I. Teratology studies and norfloxacin plasma concentrations in pregnant and nonpregnant monkeys. Teratology 1989;39:3952. As cited in Shepard TH. Catalog of Teratogenic Agents. 7th ed. Baltimore, MD: Johns Hopkins University Press, 1992:290.
4. Cukierski MA, Hendrickx AG, Prahalada S, Tarantal AF, Hess DL, Lasley BL, Peter CP, Tarara R, Robertson RT. Embryotoxicity studies of norfloxacin in cynomolgus monkeys. II. Role of progesterone. Teratology 1992;46:42938.
5. Product information. Noroxin. Merck & Company, 1997.
6. Pino A, Maura A, Villa F, Masciangelo L. Evaluation of DNA damage induced by norfloxacin in liver and kidney of adult rats and in fetal tissues after transplacental exposure. Mutat Res Lett 1991;264:815.
7. Maura A, Pino A. Induction of sperm abnormalities in mice by norfloxacin. Mutat Res Lett 1991;264:197200.
8. Berkovitch M, Pastuszak A, Gazarian M, Lewis M, Koren G. Safety of the new quinolones in pregnancy. Obstet Gynecol 1994;84:5358.
9. Pastuszak A, Andreou R, Schick B, Sage S, Cook L, Donnenfeld A, Koren G. New postmarketing surveillance data supports a lack of association between quinolone use in pregnancy and fetal and neonatal complications. Reprod Toxicol 1995;9:584.
10. 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 Biol 1996;69:839.
11. Loebstein R, Addis A, Ho E, Andreou R, Sage S, Donnenfeld AE, Schick B, Bonati M, Mortetti M, Lalkin A, Pastuszak A, Koren G. Pregnancy outcome following gestational exposure to fluoroquinolones: a multicenter prospective controlled study. Antimicrob Agents Chemother 1998;42:13369.
12. Norrby SR, Lietman PS. Safety and tolerability of fluoroquinolones. Drugs 1993;45(Suppl 3):5964.
13. Takase Z, Shirafuji H, Uchida M. Basic and clinical studies of AM-715 in the field of obstetrics and gynecology. Chemotherapy (Tokyo) 1981;29(Suppl 4):697704. As cited by Anderson PO. Drug use during breast-feeding. Clin Pharmacol 1991;10:594624.
14. Soback S, Gips M, Bialer M, Bor A. Effect of lactation on single-dose pharmacokinetics of norfloxacin nicotinate in ewes. Antimicrob Agents Chemother 1994;38:23369.

Questions and Answers

should a person who is on quinolone (norfloxacin) have a TSH test done while on the medication?, for a person suffering from urinary tract infection and on antibiotic treatment for it (norfloxacin), is it okay to have a TSH study done while on the antibiotic.

Yes, a person who is on quinolone (norfloxacin) have a TSH test done while on the medication?

Hope you liked your Y!A experience. We are experts here.

Can I use Norfloxacin to treat my urinary infectinion if I have hepatitis c. Is it safe for my liver?,

hope this helps..below is the link

There is good evidence that Bactrim (1 DS tablet daily 5 days a week) is effective in preventing spontaneous bacterial peritonitis and decreasing mortality. Norfloxacin has been used as well, but its use is discouraged because of the rapid development of resistant organisms.

Interactions between alcohol and norfloxacin?, I've read many different viewpoints on mixing alcohol and antibiotics. Lets get something straight here, I'm not looking to get drunk - but it is my friends birthday, and I rarely get a day off of work, so I would like to have a glass of wine or two. Problem being the Pharmasist didn't insert one of those interaction sheets with this medication - anyone have any specifics on Norofloxacin?

There is no interactions noted between Norfloxacin and alcohol.

Conaz: Norfloxacin & Tinidazole-- safe if I am allergive to Penicillin?, Hi,

I am in Egypt right now so I am trying to get a few opinions besides that of my doctors. I was prescribed Conaz: Norfloxacin & Tinidazole and was wondering if I can take it. I am SEVERALY allergic to Penicillin and Ceclor (and basically anything related to them). Is it safe. I am going to get in contact with my physician back home but I just wanted to get a heads up since it will be another few hours due to the time changes.

Neither drug is related to either PCN or Ceclor.

I am allergic to norfloxacin.should it mean that i am allergic to all quinolones?,

i am medical doctor
you are prone to allergic to others
best tell your family doctor

Is it OK if I've been prescribed Norfloxacin for 1 tab. - 400mg / per day?, I've been found bacteria staphylococcus aureus in my urine. I've been having some pressure like pain in my urethra and the doctor prescribed me to take Bactrim for 7 days. I took the dosage, and I feel the same, no symptoms relief. Then I went to the doctor and he prescribed me to take 1 tab. of Norfloxacin per day x 10 days in a row. Is it OK if I take only 1 tab per day, as in the manual it says to take 2 tab. per day?

do exactly as the doctor says. Also you have already had one course of an antibiotic. This is follow up dosage.

http://www.drugs.com to see the effects of this drug and others you may be also taking to see the interactions of them.

I have bacteria found in my urine?, I've been found staphylococcus aureus bacteria in my urine. The doctor prescribed me 7 days Bactrim and then 10 days Norfloxacin (only 1 pill per day). Isn't this too much antibiotics and time of treatment?

No, you should use what the doctor's said because this infection, if properly treated, can be cured.
But if you delay it, it could get worse and develop into something more serious.
So, just to be on the safe side, let the doctor be the boss!

Continue reading here: Betamethasone Risk Summary

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