Drug Safety Site.com Taking Proguanil during pregnancy and breastfeeding

• Home
• Index
• Appendix
• Instructions

PROGUANIL

Fetal Risk Summary

Although not available in the United States, proguanil, a biguanide compound that inhibits plasmodial dihydrofolate reductase, has been frequently used in other parts of the world for causal prophylaxis (defined as absolute prevention) of falciparum malaria since 1948. It is now known, however, that no chemoprophylaxis regimen ensures complete protection against infection with malaria (1). Proguanil is also indicated for the suppression of other forms of malaria and reduced transmission of infection, but because of its slow action it is not used for the acute treatment of malaria. Combination with other antimalarial agents such as chloroquine is common because of the rapid development of drug resistance. Proguanil is converted in vivo to cycloguanil, the active metabolite. Because it is a folate antagonist, pregnant women taking proguanil should also take folic acid supplements (2,3,4,5 and 6). One reviewer recommended either 5 mg/day of folic acid or 5 mg/week of folinic acid (leucovorin) at least during the 1st trimester (6). Moreover, because iron deficiency anemia is often present in some regions, a combination of proguanil, iron, and folic acid has been recommended (7).

A reproductive study in pregnant rats given proguanil and the active metabolite, cycloguanil, was summarized by Shepard (8) and also cited by Schardein (9). Proguanil, 30 mg/kg every 4 hours, was given by gavage on days 1, 9, and 13 of gestation. No effects on the embryos or fetuses were observed. In contrast, the same dose of cycloguanil on day 1 of gestation caused death in 90% of the embryos. As with proguanil, no effects were observed from exposure to cycloguanil on days 9 and 13.

Antimalarial agents, including proguanil, are used routinely during pregnancy because the risks from the disease far outweigh the risks to the fetus from drug therapy (3,4). The risks of complications from maternal malarial infection are increased during pregnancy, especially in primigravidas and in women not living in endemic areas (i.e., nonimmune women) (10,11,12 and 13). Infection is associated with a number of severe maternal and fetal outcomes: maternal death, anemia, abortion, stillbirth, prematurity, low birth weight, intrauterine growth retardation, fetal distress, and congenital malaria (10,11,12,13,14 and 15). One of these outcomes, low birth weight with the resulting increased risk of infant mortality, may have other causes, however, inasmuch as it has not been established that antimalarial chemoprophylaxis can completely prevent this complication (11). Increased maternal morbidity and mortality includes adult respiratory distress syndrome, pulmonary edema, massive hemolysis, disseminated intravascular coagulation, acute renal failure, and hypoglycemia (12,13 and 14). Severe Plasmodium falciparum malaria in pregnant nonimmune women has a poor prognosis and may be associated with asymptomatic uterine contractions, intrauterine growth retardation, fetal tachycardia, fetal distress, placental insufficiency because of intense parasitization, and hypoglycemia (11,14). Because of the severity of this disease in pregnancy, chemoprophylaxis is recommended for women of childbearing age traveling in areas where malaria is present (5,10,11 and 12).

Of 200 Nigerian women enrolled in a randomized double-blind trial, 160 were given an initial curative chloroquine course (600 mg base once), followed by prophylaxis regimens consisting of proguanil, 100 mg/day, with or without daily iron supplements or 1 mg/day of folic acid (16,17). A control group of 40 women received no treatment. All patients were primigravidas seen before 24 weeks' gestation. In the treated groups, the prevalence of falciparum parasitemia was decreased from 32%–35% to about 2% at gestational weeks 28 and 36. Benefits of the regimens that included iron and/or folic acid were reductions in (a) severe anemia during pregnancy (from 18% to 3%), (b) megaloblastic erythropoiesis at or before delivery (from 56% to 25%), and (c) anemia at 6 weeks postpartum (from 61% to 29%). However, the mean birth weight was increased by only 132 g in treated compared with untreated pregnancies (difference not significant). Other than a single case of talipes and two infants with umbilical hernias, no other birth defects were observed. The authors stated that no association with the maternal treatment groups was evident, but the groups the infants were in was not specified (16).

In the first of a series of four reports, a study published in 1993 described the use of proguanil, either alone (N=124) (200 mg once daily) or in combination with chloroquine (N=90) (300 mg base once weekly), or of chloroquine alone (N=113) (300 mg base once weekly) as malarial chemoprophylaxis during pregnancy in Tanzania (18). Chemoprophylaxis was begun after a single curative dose of pyrimethamine/sulfadoxine (Fansidar) was administered to clear preexisting parasitemia. Both proguanil chemoprophylaxis regimens were superior to chloroquine alone. The proguanil regimens were well tolerated by the mothers, with no cases of mouth ulcers and palmar or plantar skin scaling, although a few of the women complained of nausea. Based on urinary levels of proguanil and cycloguanil, they concluded that better protection from infection would have been achieved if a 12-hour dosing regimen with proguanil had been used (18).

In the second report, the effects of drug therapy on maternal hemoglobin, placental malaria, and birth weight were examined (19). As above, either proguanil alone or proguanil in combination with chloroquine were superior to chloroquine alone, producing higher levels of maternal hemoglobin, higher birth weights, and less placental malaria. The difference in outcomes between the two proguanil groups was not significant, however, leading the investigators to the conclusion that chemoprophylaxis with proguanil alone was suitable for this particular region.

The third and fourth reports in the series related to the effects of the therapy on the maternal malaria immunity and the transfer of maternal antibodies to the fetus and subsequent immunity of the offspring during early infancy (20,21). The data demonstrated that the chemoprophylaxis regimens did not significantly interfere with the maternal-fetal transfer of antisporozoite antibodies but that antibody levels at birth did not alter the first occurrence of malaria parasitemia in the infant (21).

The pharmacokinetics of proguanil in pregnant and postpartum women was described in a 1993 report (22). Ten healthy women in the 3rd trimester were given a single 200-mg oral dose and four of the women were restudied 2 months after delivery. The pharmacokinetics of proguanil during pregnancy and postpartum were similar, but the blood concentrations of the active metabolite, cycloguanil, were markedly decreased during late gestation. The mean maximum concentration (ng/mL) of cycloguanil in plasma and whole blood during pregnancy was 12.5 and 11.9, respectively, compared with postpartum levels of 28.4 and 22.4, respectively. Moreover, the proguanil:cycloguanil ratio based on the area under the plasma concentration curve (AUC) was 16.7 during pregnancy and 7.8 following pregnancy. The decreased conversion to the active antimalarial metabolite may have been caused by estrogen inhibition of the enzyme that metabolizes proguanil (22). Although the antimalarial prophylaxis concentration of cycloguanil is not known with certainty, these data indicate that the currently recommended dose of 200 mg/day may need to be doubled during late pregnancy to achieve the same blood levels as those obtained 2 months postpartum (22).

In summary, no adverse fetal or newborn effects attributable to the use of proguanil during gestation have been reported. It is considered by some to be the least toxic prophylactic agent available (23). Moreover, most investigators have concluded that proguanil is safe to use during pregnancy (1,2,3,4,5 and 6,10,18,23,24 and 25).

Breast Feeding Summary

No reports quantifying the amount of proguanil excreted in breast milk have been located. At least two reports have stated that agents used for malaria prophylaxis, such as proguanil, are excreted in small amounts in milk (2,10). These amounts, however, are too small for adequate malaria chemoprophylaxis of a nursing infant (2,10). Because proguanil is recommended for malaria protection in infants of any age (2,10,25), the use of the agent by a nursing woman is probably safe. Studies are needed, however, to measure the amount of proguanil and the active metabolite, cycloguanil, in milk and to determine the safety of this exposure in the nursing infant.

References

1. Barry M, Bia F. Pregnancy and travel. JAMA 1989;261:728–31.
2. Luzzi GA, Peto TEA. Adverse effects of antimalarials. An update. Drug Saf 1993;8:295–311.
3. Cook GC. Prevention and treatment of malaria. Lancet 1988;1:32–7.
4. Bradley DJ, Phillips-Howard PA. Prophylaxis against malaria for travellers from the United Kingdom. Br Med J 1989;299:1087–9.
5. Ellis CJ. Antiparasitic agents in pregnancy. Clin Obstet Gynaecol 1986;13:269–75.
6. Spracklen FHN. Malaria 1984. Part I. Malaria prophylaxis. S Afr Med J 1984;65:1037–41.
7. Fleming AF. The aetiology of severe anaemia in pregnancy in Ndola, Zambia. Ann Trop Med Parasitol 1989;83:37–49.
8. Shepard TH. Catalog of Teratogenic Agents. 8th ed. Baltimore, MD: Johns Hopkins University Press, 1995:118.
9. Schardein JL. Chemically Induced Birth Defects. 2nd ed. New York, NY: Marcel Dekker, 1993:403.
10. Centers for Disease Control. Recommendations for the prevention of malaria among travelers. MMWR 1990;39(RR-3):1–10.
11. World Health Organization. Practical chemotherapy of malaria. WHO Tech Rep Ser 1990;805:1–141.
12. Subramanian D, Moise KJ Jr, White AC Jr. Imported malaria in pregnancy: report of four cases and review of management. Clin Infect Dis 1992;15:408–13.
13. World Health Organization. Severe and complicated malaria. Trans R Soc Trop Med Hyg 1990;84(Suppl 2):1–65.
14. Nathwani D, Currie PF, Douglas JG, Green ST, Smith NC. Plasmodium falciparum malaria in pregnancy: a review. Br J Obstet Gynaecol 1992;99:118–21.
15. Steketee RW, Wirima JJ, Slutsker L, Heymann DL, Breman JG. The problem of malaria and malaria control in pregnancy in sub-Saharan Africa. Am J Trop Med Hyg 1996;55(Suppl):2–7.
16. Fleming AF, Ghatoura GBS, Harrison KA, Briggs ND, Dunn DT. The prevention of anaemia in pregnancy in primigravidae in the Guinea Savanna of Nigeria. Ann Trop Med Parasitol 1986;80:211–33.
17. Fleming AF. Antimalarial prophylaxis in pregnant Nigerian women. Lancet 1990;335:45.
18. Mutabingwa TK, Malle LN, de Geus A, Oosting J. Malaria chemosuppression in pregnancy. I. The effect of chemosuppressive drugs on maternal parasitaemia. Trop Geogr Med 1993;45:6–14.
19. Mutabingwa TK, Malle LN, de Geus A, Oosting J. Malaria chemosuppression in pregnancy. II. Its effect on maternal haemoglobin levels, placental malaria and birth weight. Trop Geogr Med 1993;45:49–55.
20. Mutabingwa TK, Malle LN, Eling WMC, Verhave JP, Meuwissen JHETh, de Geus A. Malaria chemosuppression in pregnancy. III. Its effects on the maternal malaria immunity. Trop Geogr Med 1993;45:103–9.
21. Mutabingwa TK, Malle LN, Verhave JP, Eling WMC, Meuwissen JHETh, de Geus A. Malaria chemosuppression during pregnancy. IV. Its effects on the newborn's passive malaria immunity. Trop Geogr Med 1993;45:150–6.
22. Wangboonskul J, White NJ, Nosten F, ter Kuile F, Moody RR, Taylor RB. Single dose pharmacokinetics of proguanil and its metabolites in pregnancy. Eur J Clin Pharmacol 1993;44:247–51.
23. Olsen VV. Why not proguanil in malaria prophylaxis? Lancet 1983;1:649.
24. Anonymous. Malaria in pregnancy. Lancet 1983;2:84–5.
25. Anonymous. Prevention of malaria in pregnancy and early childhood. Br Med J 1984;289:1296–7.
    
    

Q&A about Proguanil

Index

A  B  C  D  E  F  G  H  I  K  L  M  N  O  P  Q  R  S  T  U  V  W  Z

Popular Meds

• Acyclovir
• Allopurinol
• Alprazolam
• Amiodarone
• Amitriptyline
• Amoxicillin
• Atenolol
• Atorvastatin
• Azithromycin
• Bupropion
• Buspirone
• Butalbital
• Carisoprodol
• Cefixime
• Celecoxib
• Cephalexin
• Cetirizine
• Ciprofloxacin
• Clomiphene
• Clonazepam
• Clonidine
• Codeine
• Cyclobenzaprine
• Diazepam
• Diethylpropion
• Diltiazem
• Doxycycline
• Enalapril
• Ephedrine
• Erythromycin
• Estradiol
• Fluconazole
• Fluoxetine
• Furosemide
• Gitalin
• Hydrocodone
• Lorazepam
• Losartan
• Metformin
• Metronidazole
• Minoxidil
• Naproxen
• Ondansetron
• Oxycodone
• Pantoprazole
• Passion Flower
• Phendimetrazine
• Phentermine
• Pioglitazone
• Pravastatin
• Propranolol
• Pseudoephedrine
• Quinine
• Ramipril
• Ranitidine
• Rosiglitazone
• Sertraline
• Simvastatin
• Sumatriptan
• Tamoxifen
• Terbinafine
• Tetracycline
• Thyroid
• Tramadol
• Trazodone
• Valerian
• Vitamin C
• Zolpidem

Copyright © 2003-2008 DRUGSAFETYSITE.COM All rights reserved.