Antiprotozoal
PREGNANCY RECOMMENDATION: Compatible—Maternal Benefit >> Embryo–Fetal Risk
BREASTFEEDING RECOMMENDATION: No Human Data—Potential Toxicity
PREGNANCY SUMMARY
The use of atovaquone, usually combined with proguanil (see also Proguanil), during human pregnancy does not appear to increase the risk of major birth defects. The lack of toxicity in animals with doses close to those used in humans is reassuring. Two reviews, one in 2004 (1) and the other in 2011 (2), concluded that the drug could be used in pregnancy. Because the maternal benefit appears to exceed the unknown embryo–fetal risk, the agent should not be withheld because of pregnancy.
FETAL RISK SUMMARY
Atovaquone is an analog of ubiquinone that is indicated for the prevention and treatment of Pneumocystis carinii pneumonia in patients intolerant of trimethoprim–sulfamethoxazole (3). The agent, when combined with proguanil, is also indicated for the prevention and treatment of malaria due to Plasmodium falciparum (2,4). Unlabeled uses include the treatment of babesiosis (in combination with quinine and/or clindamycin and/or azithromycin) and toxoplasmosis (in combination with pyrimethamine) (5). The drug undergoes little, if any, metabolism and is extensively bound (99.9%) to plasma proteins. The elimination half-life is long, ranging from about 67–78 hours (3).
Reproduction studies have been conducted in rats and rabbits (3,4). In rats, no teratogenicity or reproductive toxicity was observed at plasma concentrations 2–3 times the estimated human exposure (HE) for P. carinii (3) or 5–6.5 times the HE for malaria (4). In rabbits, plasma concentrations about 0.5 times the HE for P. carinii (3) and 0.6–1.3 times the HE for malaria (4) were maternally toxic. At these exposures, mean fetal body weights and lengths were decreased, and there were higher numbers of early resorption and post-implantation losses. These effects may have been due to the maternal toxicity (3,4). The combination of atovaquone and proguanil was not teratogenic in rats (1.7 and 0.10 times the HE for malaria, respectively) or rabbits (0.34 and 0.82 times the HE for malaria, respectively). There was also no embryotoxicity in rabbits at these exposures (4).
Atovaquone was not carcinogenic in rats, but hepatocellular adenoma and carcinoma were observed with all doses tested in mice (1.4–3.6 times the average plasma concentrations in humans). In other tests, there was no evidence of atovaquone-induced mutagenicity or genotoxicity (3).
It is not known if atovaquone crosses the human placenta. The molecular weight (about 367), absence of metabolism, and long elimination half-life suggest that atovaquone will cross the human placenta to the embryo–fetus. However, the extensive plasma protein binding might limit the amount that crosses.
In an antenatal clinic in Thailand, 24 pregnant women who had tested positive for malaria were treated with a triple combination of atovaquone (20 mg/kg/day), proguanil (8 mg/kg/day), and artesunate (4 mg/kg/day) for 3 days (5). The study was conducted to determine the pharmacokinetic properties of the drugs in pregnancy. The median estimated gestational age at the start of treatment was 28.5 weeks (range 19.1–35.9 weeks). No adverse effects of the therapy were observed in the fetuses or newborns (5).
Some of the same authors in the above report used the identical regimen to treat 27 pregnant women with multidrug-resistant malaria (6). The treatment occurred at a mean gestational age of 28.2 weeks. They found no evidence of toxicity in the mothers or the fetuses (6).
The 3-day triple anti-infective regimen described above was compared with a 7-day supervised trial of quinine for the treatment of uncomplicated falciparum malaria (7). There were 39 pregnant women in the three-drug group and 42 in the one-drug group. All of the women were in the 2nd or 3rd trimesters. The three-drug regimen was significantly better and had a much lower failure rate. There were no significant differences in pregnancy duration, birth weight, congenital anomalies, or in growth and development of infants monitored for 1 year (7).
A combination tablet containing atovaquone 250 mg and proguanil 100 mg was used to treat 26 women (gestational age 24–34 weeks) with acute uncomplicated P. falciparum malaria (8). The study was designed to determine the pharmacokinetics of the two drugs and cycloguanil, the active metabolite of proguanil. No serious toxicities were observed and the newborns had no physical anomalies (8).
A large nationwide cohort study from Denmark, covering the period 2000–2008, compared the pregnancy outcomes (live births) of women exposed to atovaquone–proguanil during the 1st trimester with those not exposed (9). In weeks 3–8 after conception, 93 were exposed (1 major birth defect, 1.1%) compared with 570,784 unexposed (13,994 major birth defects, 2.5%). The adjusted prevalence odds ratio (POR) was 0.43 and 95% confidence interval (CI) 0.06–3.11. For exposure anytime in the 1st trimester, 149 were exposed (2 major birth defects, 1.3%) compared with 570,728 unexposed (13,993 major birth defects, 2.5%), POR 0.55, and 95% CI 0.14–2.21. The birth defects were those observed in the first year of life (9).
BREASTFEEDING SUMMARY
No reports describing the use of atovaquone during lactation have been located. The molecular weight (about 367), absence of metabolism, and long elimination half-life (about 67–78 hours) suggest that the drug will be excreted into breast milk. However, the extensive plasma protein binding (99.9%) should limit the amount in milk. The effect of this exposure on a nursing infant is unknown. The severity of the mother’s illness, such as infection with HIV, may preclude breastfeeding. In addition, the potential for severe adverse effects in a nursing infant, such as gastrointestinal symptoms, rash, fever, headache, hepatic toxicity, and carcinogenicity, suggests that even HIV-negative women should not breastfeed if they are taking this drug.
References
1.Rosenblatt JE. Antiparasitic agents. Mayo Clin Proc 1999;74:1161–75.
2.Irvine MH, Einarson A, Bozzo P. Prophylactic use of antimalarials during pregnancy. Can Fam Physician 2011;57:1279–81.
3.Product information. Mepron. GlaxoSmithKline, 2004.
4.Product information. Malarone. GlaxoSmithKline, 2004.
5.McGready R, Stepniewska K, Edstein MD, Cho T, Gilveray G, Looareesuwan S, White NJ, Nosten F. The pharmacokinetics of atovaquone and proguanil in pregnant women with acute falciparum malaria. Eur J Clin Pharmacol 2003;59:545–52.
6.McGready R, Keo NK, Villegas L, White NJ, Looareesuwan S, Nosten F. Artesunate-atovaquone-proguanil rescue treatment of multidrug-resistant Plasmodium falciparum malaria in pregnancy: a preliminary report. Trans R Soc Trop Med Hyg 2003;97:592–4.
7.McGready R, Ashley EA, Moo E, Cho T, Barends M, Hutagalung R, Looareesuwan S, White NJ, Nosten F. A randomized comparison of artesunate-atovaquone-proguanil versus quinine in treatment of uncomplicated falciparum malaria during pregnancy. J Infect Dis 2005;192:846–53.
8.Na-Bangchang K, Manyando C, Ruengweerayut R, Kioy D, Mulenga M, Miller GB, Konsil J. The pharmacokinetics and pharmacodynamics of atovaquone and proguanil for the treatment of uncomplicated falciparum malaria in third-trimester pregnant women. Eur J Clin Pharmacol 2005;61:573–82.
9.Pasternak B, Hviid A. Atovaquone-proguanil use in early pregnancy and the risk of birth defects. Arch Intern Med 2011;171:259–60.