Anti-infective (Antiprotozoal)
PREGNANCY RECOMMENDATION: Limited Human Data—Animal Data Suggest Moderate Risk
BREASTFEEDING RECOMMENDATION: Hold Breastfeeding (Single Dose)
Limited Human Data—Potential Toxicity (Divided Dose)
PREGNANCY SUMMARY
The human pregnancy experience with tinidazole is very limited. Although there was a slight increase in fetal deaths in one animal species at a dose close to that used in humans, no other evidence of developmental toxicity was noted in animal studies. Tinidazole is chemically related to metronidazole, and there is no convincing evidence of embryo or fetal harm with that anti-infective. Nevertheless, it would be prudent to choose metronidazole for those infections where both agents are recommended. Tinidazole could be used in cases where metronidazole therapy has failed to eradicate the infection. However, until more human data are available, avoidance of the 1st trimester should be considered.
FETAL RISK SUMMARY
Tinidazole is an oral synthetic antiprotozoal agent that chemically is a second-generation 5-nitroimidazole. It is closely related structurally to metronidazole. Tinidazole is indicated for the treatment of trichomoniasis caused by Trichomonas vaginalis, giardiasis caused by Giardia duoenalis, and amebiasis caused by Entamoeba histolytica. Oral bioavailability is 100%. It is partially metabolized and has a plasma half-life of about 12–14 hours. Plasma protein binding of tinidazole is about 12% (1).
Reproduction studies have been conducted in mice and rats. In pregnant mice, no evidence of embryo or fetal harm was observed with doses up to about 6.3 times the maximum human therapeutic dose based on BSA (MHTD). In pregnant rats, a slightly higher incidence of fetal death was noted with a dose 2.5 times the MHTD. No biologically relevant neonatal developmental effects were noted in rat pups after maternal doses as high as 3 times the MHTD (1).
Long-term studies for carcinogenic effects have not been conducted with tinidazole. A closely related agent, metronidazole, has been studied and found to be associated with tumors in mice and rats (1) (see also Metronidazole). Assays for mutagenicity with tinidazole have resulted in both positive and negative results (1).
Decreased fertility and testicular histopathology occurred in male rats given doses that were about 3 times the MHTD for 60 days. Spermatogenic effects were noted at doses that were about ≥1.5 times the MHTD. The no-observed-adverse-effect level for testicular and spermatogenic effects was about half the MHTD. These findings are characteristic of agents in the 5-nitroimidazole class (1).
Tinidazole crosses the human placenta. A single 500-mg IV infusion was given over 20 minutes to 11 women undergoing a 1st trimester abortion (2). Sixty minutes after the start of the infusion, the uterus was evacuated. The mean concentrations of tinidazole in the maternal serum, fetal tissue, and placental tissue were 13.2 mcg/mL, 7.6 mcg/g, and 4.9 mg/g, respectively. The fetal tissue level was 58% of the maternal serum concentration (2).
The large population-based dataset of the Hungarian Case–Control Surveillance of Congenital Abnormalities was used to evaluate the effect of oral tinidazole (1–2 g/day for 6–7 days) on pregnancy outcomes in terms of congenital defects (3). Among the 22,843 cases with congenital anomalies, 10 (0.04%) had taken tinidazole, whereas in 38,151 controls, 16 (0.04%) had been exposed to the drug. The exposures had occurred in the 1st trimester in six cases and six controls. Although the data are very limited, there was no suggestion that tinidazole exposures resulted in a higher rate of congenital anomalies (3).
A 2006 review of the treatment of trichomoniasis concluded that single, 2-g oral dose of either metronidazole or tinidazole were first-line therapy (4). If a decision was made to treat a pregnant woman, metronidazole was preferred because of the greater amount of data related to pregnancy.
According to the CDC’s 2006 Sexually Transmitted Diseases Treatment guidelines, recurrent and persistent urethritis was best treated with single, 2-g oral dose of either metronidazole or tinidazole (5). No special consideration was made for pregnancy. A similar recommendation was made for trichomoniasis. In this case, however, the limited human pregnancy experience with tinidazole was mentioned (5).
BREASTFEEDING SUMMARY
Tinidazole is excreted into breast milk. In a 1972 report, four women had milk:serum ratios as high as 1.62 after 7 days of treatment with tinidazole (6). A 1983 investigation studied the milk excretion of the drug in 24 women (7). After cord clamping, an IV infusion of tinidazole 500 mg was given to the mother over 20 minutes. Milk (colostrum) and blood samples were collected at 12, 24, 48, 72, and 96 hours after the end of the infusion. Mean maternal serum concentrations (mcg/mL) in the five samples were 6.1, 3.7, 1.2, 0.1, and 0, respectively. Milk samples at 12 and 24 hours were mixed samples, whereas the samples at 48, 72, and 96 hours were collected as fore- and hind-milk. The mixed milk concentrations were 5.8 and 3.5 mcg/mL, respectively. At the three other times, the concentrations (fore-milk/hind-milk) were 1.28/1.20, 0.32/0.30, and trace/trace, respectively. It was not stated if the infants were allowed to breastfeed (7).
In a 1985 study, five women undergoing a cesarean section received a single IV dose of tinidazole 1600 mg infused within 1.5 hours immediately after cord clamping (8). Blood and milk samples were collected at 8- and 4-hour intervals, respectively, for 96 hours. The average half-life of tinidazole in serum was 11.4 hours. The milk:serum ratios ranged from 0.62 to 1.39 with milk concentrations highly related to serum concentrations (r = 0.969). By 72 hours, only one woman had a milk concentration greater than 0.5 mcg/mL. The infants were not allowed to breastfeed. It was estimated that at 72 hours, the maximum daily dose for a nursing infant would be 0.1 mg/kg (assuming 3.5 kg body weight and 400 mL of milk consumed), and that breastfeeding then could commence (8).
The effect of exposure to tinidazole in breast milk is unknown because none of the above mothers breastfed their infants. Because of the close similarity between tinidazole and metronidazole, the American Academy of Pediatrics classifies both drugs as agents whose effect on nursing infants is unknown but may be of concern (9). If single-dose therapy is given, discontinuing breastfeeding for 12–24 hours to allow excretion of the drug was recommended.
References
1.Product information. Tindamaz. Presutti Laboratories, 2004.
2.Karhunen M. Placental transfer of metronidazole and tinidazole in early human pregnancy after a single infusion. Br J Clin Pharmacol 1984;18:254–7.
3.Czeizel AE, Kazy Z, Vargha P. Oral tinidazole treatment during pregnancy and teratogenesis. Int J Gynecol Obstet 2003;83:305–6.
4.Nanda N, Michel RG, Kurdgelashvili G, Wendel KA. Trichomoniasis and its treatment. Expert Rev Anti Infect Ther 2006;4:125–35.
5.CDC. Sexually transmitted diseases treatment guidelines, 2006. MMWR 2006;55(RR11):1–94.
6.Welling PG, Monro AM. The pharmacokinetics of metronidazole and tinidazole in man. Arzneimittelforsch 1972;22:2128–32. As cited in Mannisto PT, Karhunen M, Koskela O, Suikkari AM, Mattila J, Haataja H. Concentrations of tinidazole in breast milk. Acta Pharmacol Toxicol (Copenh) 1983;53:254–6.
7.Mannisto PT, Karhunen M, Koskela O, Suikkari AM, Mattila J, Haataja H. Concentrations of tinidazole in breast milk. Acta Pharmacol Toxicol (Copenh) 1983;53:254–6.
8.Evaldson GR, Lindgren S, Nord CE, Rane AT. Tinidazole milk excretion and pharmacokinetics in lactating women. Br J Clin Pharmacol 1985;19:503–7.
9.Committee on Drugs, American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 2001;108:776–89.