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MEFLOQUINE

Fetal Risk Summary

Mefloquine is a quinoline-methanol antimalarial agent used in the prevention and treatment of malaria caused by Plasmodium falciparum, including chloroquine-resistant strains, or by Plasmodium vivax. At high doses (80–160 mg/kg/day), mefloquine is teratogenic in mice, rats, and rabbits, and, at one dose (160 mg/kg/day), it is embryotoxic in rabbits (1). Smaller doses (20–50 mg/kg/day) impaired fertility in rats, but no adverse effect was observed on spermatozoa in humans taking 250 mg/week for 22 weeks (1).

A study published in 1990 examined the pharmacokinetics of mefloquine during the 3rd trimester of pregnancy (2). Twenty women were treated with either 250 mg of mefloquine base (N=10) or 125 mg of base (N=10) weekly until delivery at term. Peak and trough concentrations of mefloquine were lower than those measured in nonpregnant adults, and the terminal elimination half-life was 11.6 ± 7.9 days. The half-life reported in nonpregnant adults is 15–33 days (1). No obstetric complications were observed at either dosage level, including during labor, and no toxicity was observed in the exposed infants. Normal infant development was observed during a 2-year follow-up.

The risks of complications from malarial infection occurring during pregnancy are increased, especially in women not living in endemic areas (i.e., nonimmune women) (3,4,5 and 6). Infection is associated with a number of severe maternal and fetal outcomes: maternal death, anemia, abortion, stillbirth, prematurity, low birth weight, fetal distress, and congenital malaria (3,4,5,6 and 7). However, one of these outcomes, low birth weight with the resulting increased risk of infant mortality, may have other causes inasmuch as it has not been established that antimalarial chemoprophylaxis can prevent this complication (4). Increased maternal morbidity and mortality includes adult respiratory distress syndrome, pulmonary edema, massive hemolysis, disseminated intravascular coagulation, acute renal failure, and hypoglycemia (5,6 and 7). Severe P. 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 (4,7). The exacerbation of this latter adverse effect has not been reported with mefloquine (7), but it occurs frequently with quinine (7,8 and 9). Because of the severity of this disease in pregnancy, chemoprophylaxis is recommended for women of childbearing age traveling in areas where malarial is present (3,4 and 5). However, some authors state that mefloquine should not be used for prophylaxis during pregnancy, especially during the 1st trimester, because of the potential for fetotoxicity (3,4 and 5,7,10,11,12,13 and 14), except in areas where chloroquine-resistant P. falciparum is present (11). An editorial comment to one Reference stated that recent data indicated the use of mefloquine during early pregnancy could result in congenital defects, but no other information was provided (15).

Two reports have described the therapeutic use of mefloquine during pregnancy without causing adverse fetal effects (4,16). A 24-year-old woman presented at 33 weeks' gestation with fever, scleral icterus, and tender splenomegaly secondary to P. falciparum infection involving 3% of her erythrocytes (16). After two attempts to administer doses of mefloquine (750 and 500 mg), both of which were vomited, predosing with IV metoclopramide allowed the woman to tolerate three 250-mg doses spaced 4 hours apart and two 250-mg doses the following day (total dose 1250 mg). Maternal fever resolved the day after therapy and, at 5 days, no parasites were observed in the mother's blood. Two months later, a 3405-g infant (sex not specified) was delivered by cesarean section for pelvic disproportion and poor beat-to-beat fetal heart rate variability. Apgar scores at 1 and 5 minutes were 6 and 9, respectively. The child was developing normally at 2 months.

An unpublished double-blind, randomized, controlled study from Thailand conducted between 1983 and 1989 was briefly described in a World Health Organization (WHO) publication (4) and a 1993 review (13). A total of 178 pregnant women were randomized to two groups; one group received mefloquine 500 mg every 8 hours for two doses (N=87), and the other group received quinine 600 mg every 8 hours for 7 days (N=91). Although the exact stages of pregnancy at the time of treatment were not specified, a small number of the women in the mefloquine group were in the 1st trimester (4,13). All of the women were followed to term. The incidence of uterine contractions, premature labor, and fetal distress in the mefloquine and quinine groups were 18% vs. 25%, 1% vs. 5%, and 2% vs. 4%, respectively (4). None of the differences were statistically significant. No stillbirths occurred, but one spontaneous abortion was observed in each group, 21 days after mefloquine and 37 days after quinine; neither was thought to be related to drug treatment (4). The 21-day cure rate was 97% among those treated with mefloquine compared with 86% of those treated with quinine. Three newborns had congenital malformations, but these were believed to be unrelated to the drug therapy (13). The study investigators concluded that the therapeutic use of mefloquine during pregnancy was safe and effective. The WHO Scientific Group concluded, however, that, because of the small number of patients, treatment with mefloquine should be undertaken cautiously during the first 12–14 weeks of gestation (4).

Two trials of mefloquine prophylaxis in pregnancy were reviewed in a 1993 Reference (13). An unpublished study compared weekly prophylaxis with either mefloquine (N=468) or chloroquine (N=1312) in asymptomatic pregnant women (13). Mefloquine was more effective than chloroquine in preventing fetal growth retardation and was also effective in reducing placental P. falciparum infections. In another double-blind, placebo-controlled trial, prophylaxis during the second half of pregnancy with 250 mg/week for 1 month followed by 125 mg/week until delivery in 360 Karen women was 95% effective in preventing malaria (13). The incidence of stillbirths was similar between mefloquine (N=4) and placebo (N=5).

A presentation made at a 1991 conference described the follow-up of 98 prospectively recorded pregnancy exposures to mefloquine (17). Five diverse congenital malformations were observed, an incidence that does not support mefloquine-induced teratogenicity.

Breast Feeding Summary

Mefloquine is excreted in human milk (1,18). Two women, who were not breast-feeding, were given a single 250-mg dose, 2–3 days after delivery (18). Milk samples were collected from both women during the first 4 days after dosing, and from one woman at various intervals up to 56 days. The milk:plasma ratios in the two women during the first 4 days were 0.13 and 0.16, respectively. In one woman, the ratio was 0.27 calculated over 56 days. The investigators estimated that a 4-kg infant consuming 1000 mL of milk daily would ingest 0.08 mg/day of the mother's dose (18), or approximately 4% of the dose would be recovered from the milk (1,18). Although these amounts are not thought to be harmful to the nursing infant, they are insufficient to provide adequate protection against malaria (3).

Long-term effects of mefloquine exposure via breast milk have not been studied. Because the antimalarial agent has a long plasma half-life, averaging nearly 12 days during pregnancy (2) and 14.4–18.0 days during and after lactation (18), weekly prophylactic doses of mefloquine will result in continuous exposure of a nursing infant. Moreover, higher milk concentrations of mefloquine than those reported should be expected after therapeutic or weekly prophylactic doses (18).

References

1. Product information. Lariam. Roche Laboratories, 1993.
2. Nosten F, Karbwang J, White NJ, Honeymoon, Na Bangchang K, Bunnag D, Harinasuta T. Mefloquine antimalarial prophylaxis in pregnancy: dose finding and pharmacokinetic study. Br J Clin Pharmacol 1990;30:79–85.
3. Centers for Disease Control. Recommendations for the prevention of malaria among travelers. MMWR 1990;39:1–10.
4. World Health Organization. Practical chemotherapy of malaria. WHO Tech Rep Ser 1990;805:1–141.
5. 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.
6. World Health Organization. Severe and complicated malaria. Trans R Soc Trop Med Hyg 1990;84(Suppl 2):1–65.
7. 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.
8. Phillips RE, Looareesuwan S, White NJ, Silamut K, Kietinun S, Warrell DA. Quinine pharmacokinetics and toxicity in pregnant and lactating women with falciparum malaria. Br J Clin Pharmacol 1986;21:677–83.
9. White NJ, Warrell DA, Chanthavanich P, Looareesuwan S, Warrell MJ, Krishna S, Williamson DH, Turner RC. Severe hypoglycemia and hyperinsulinemia in falciparum malaria. N Engl J Med 1983;309:61–6.
10. Bradley D. Prophylaxis against malaria for travellers from the United Kingdom. Br Med J 1993;306:1247–52.
11. Barry M, Bia F. Pregnancy and travel. JAMA 1989;261:728–31.
12. Lackritz EM, Lobel HO, Howell BJ, Bloland P, Campbell CC. Imported Plasmodium falciparum malaria in American travelers to Africa. JAMA 1991;265:383–5.
13. Palmer KJ, Holliday SM, Brogden RN. Mefloquine. A review of its antimalarial activity, pharmacokinetic properties and therapeutic efficacy. Drugs 1993;45:430–75.
14. Baker L, Van Schoor JD, Bartlett GA, Lombard JH. Malaria prophylaxis—the South African viewpoint. S Afr Med J 1993;83:126–9.
15. Raccurt CP, Le Bras M, Ripert C, Cuisinier-Raynal JC, Carteron B, Buestel ML. Paludisme d'importation à Bordeaux: évaluation du risque d'infectation par Plasmodium falciparum en fonction de la destination. Bull WHO 1991;69:85–91.
16. Collignon P, Hehir J, Mitchell D. Successful treatment of falciparum malaria in pregnancy with mefloquine. Lancet 1989;1:967.
17. Elefant E, Boyer M, Roux C. Presentation at the 4th International Conference of Teratogen Information Services, Chicago, Il., April 18–20, 1991 (F Rosa, personal communication, 1993).
18. Edstein MD, Veenendaal JR, Hyslop R. Excretion of mefloquine in human breast milk. Chemotherapy (Basel) 1988;34:165–9.
    
    

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