Proguanil/Atovaquone

Pregnancy

8.1 Pregnancy Risk Summary Available data from published literature and postmarketing experience with use of atovaquone and proguanil hydrochloride tablets in pregnant women are insufficient to identify a drug-associated risk for major birth defects, miscarriage, or adverse maternal or fetal outcomes. The proguanil component of atovaquone and proguanil hydrochloride tablets acts to inhibit parasitic dihydrofolate reductase; however, pregnant women and females of reproductive potential should continue folate supplementation to prevent neural tube defects [see Clinical Pharmacology (12.4) ] . Pregnant women with malaria are at increased risk for adverse pregnancy outcomes (see Clinical Considerations ) . Atovaquone administered by oral gavage to pregnant rats and rabbits during the period of organogenesis was not associated with fetal malformations at plasma exposures approximately 7 times and equal to, respectively, the estimated human exposure for the treatment of malaria based on AUC. Proguanil administered to pregnant rats and rabbits during the period of organogenesis was not associated with embryo-fetal toxicity at maternally toxic plasma exposures approximately 0.07 and 0.8 times, respectively, the estimated human exposure for treatment of malaria based on AUC (see Data ) . The combination of atovaquone and proguanil hydrochloride given orally by gavage during the period of organogenesis was not associated with embryo-fetal developmental effects in pregnant rats or rabbits at atovaquone:proguanil hydrochloride doses of 50:20 mg/kg/day and 100:40 mg/kg/day, respectively (1.7 and 0.1 times and 0.3 and 0.5 times, respectively, the estimated human exposure for treatment of malaria). In a pre- and post-natal study with atovaquone and another pre- and post-natal study with proguanil, neither compound impaired the growth, development, or reproductive ability of first generation offspring at maternal AUC exposures of approximately 7.3 and 0.04 times, respectively, the estimated human AUC exposure for treatment of malaria (see Data ) . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Malaria during pregnancy increases the risk for adverse pregnancy outcomes, including maternal anemia, prematurity, spontaneous abortion, and stillbirth. Data Animal Data Atovaquone Atovaquone administered in oral doses of 250, 500, and 1,000 mg/kg/day during organogenesis (Gestation Day [GD] 6 to GD15) in pregnant rats did not cause maternal or embryo-fetal toxicity at doses up to 1,000 mg/kg/day corresponding to maternal plasma exposures up to 7.3 times the estimated human exposure for the treatment of malaria based on AUC. In pregnant rabbits, atovaquone administered in oral doses of 300, 600, and 1,200 mg/kg/day by gavage during organogenesis (GD6 to GD18) was associated with decreased fetal body length at a maternally toxic dose of 1,200 mg/kg/day corresponding to plasma exposures that were approximately 1.3 times the estimated human exposure during treatment of malaria based on AUC. In a pre- and post-natal study in rats, atovaquone administered in oral doses of 250, 500, and 1,000 mg/kg/day from GD15 until Lactation Day (LD) 20 did not impair the growth or developmental effects in first generation offspring at doses up to 1,000 mg/kg/day corresponding to AUC exposures of approximately 7.3 times the estimated human exposure during treatment of malaria. Atovaquone crossed the placenta and was present in fetal rat and rabbit tissue. Proguanil Proguanil administered orally to pregnant rats during organogenesis (GD6 to GD17) was not associated with fetal malformations, but increased ureter variations at a maternally toxic dose of 20 mg/kg/day corresponding to a plasma concentration approximately equal to 0.07 times the estimated human exposure for the treatment of malaria based on AUC. Proguanil given orally by gavage at a maternally toxic dose of 40 mg/kg/day to pregnant rabbits during organogenesis (GD6 to GD20) did not produce adverse embryo-fetal effects at a plasma concentration up to 0.8 times the estimated human exposure for the treatment of malaria based on AUC. In a pre- and post-natal study in female rats, proguanil hydrochloride administered in oral doses of 4, 8, or 16 mg/kg/day from GD6 until LD20 did not impair the growth, development, or reproductive ability of first generation offspring or the survivability of second generation offspring at doses up to 16 mg/kg/day (0.04 times the average human exposure based on AUC). Pre- and post-natal studies of proguanil in animals at exposures similar to or greater than those observed in humans have not been conducted. Atovaquone and Proguanil The combination of atovaquone and proguanil hydrochloride administered orally to pregnant rats in atovaquone:proguanil hydrochloride doses of 12.5:5, 25:10, and 50:20 mg/kg/day during organogenesis (GD6 to GD17) did not produce maternal toxicity or adverse embryo-fetal developmental effects with doses up to 50:20 mg/kg/day corresponding to plasma concentrations up to 1.7 and 0.1 times, respectively, the estimated human exposure during treatment of malaria based on AUC. In pregnant rabbits, the combination of atovaquone and proguanil hydrochloride administered orally in atovaquone:proguanil hydrochloride doses of 25:10, 50:20, or 100:40 mg/kg/day during organogenesis (GD6 to GD20) did not produce adverse embryo-fetal developmental effects at a maternally toxic dose of 100:40 mg/kg/day corresponding to plasma concentrations of approximately 0.3 and 0.5 times, respectively, the estimated human exposure during treatment of malaria based on AUC.

Lactation

impairment: contraindicated for prophylaxis of P. falciparum malaria in patients with severe renal impairment. ( 8.6 ) 8.1 Pregnancy Risk Summary Available data from published literature and postmarketing experience with use of atovaquone and proguanil hydrochloride tablets in pregnant women are insufficient to identify a drug-associated risk for major birth defects, miscarriage, or adverse maternal or fetal outcomes. The proguanil component of atovaquone and proguanil hydrochloride tablets acts to inhibit parasitic dihydrofolate reductase; however, pregnant women and females of reproductive potential should continue folate supplementation to prevent neural tube defects [see Clinical Pharmacology (12.4) ] . Pregnant women with malaria are at increased risk for adverse pregnancy outcomes (see Clinical Considerations ) . Atovaquone administered by oral gavage to pregnant rats and rabbits during the period of organogenesis was not associated with fetal malformations at plasma exposures approximately 7 times and equal to, respectively, the estimated human exposure for the treatment of malaria based on AUC. Proguanil administered to pregnant rats and rabbits during the period of organogenesis was not associated with embryo-fetal toxicity at maternally toxic plasma exposures approximately 0.07 and 0.8 times, respectively, the estimated human exposure for treatment of malaria based on AUC (see Data ) . The combination of atovaquone and proguanil hydrochloride given orally by gavage during the period of organogenesis was not associated with embryo-fetal developmental effects in pregnant rats or rabbits at atovaquone:proguanil hydrochloride doses of 50:20 mg/kg/day and 100:40 mg/kg/day, respectively (1.7 and 0.1 times and 0.3 and 0.5 times, respectively, the estimated human exposure for treatment of malaria). In a pre- and post-natal study with atovaquone and another pre- and post-natal study with proguanil, neither compound impaired the growth, development, or reproductive ability of first generation offspring at maternal AUC exposures of approximately 7.3 and 0.04 times, respectively, the estimated human AUC exposure for treatment of malaria (see Data ) . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Malaria during pregnancy increases the risk for adverse pregnancy outcomes, including maternal anemia, prematurity, spontaneous abortion, and stillbirth. Data Animal Data Atovaquone Atovaquone administered in oral doses of 250, 500, and 1,000 mg/kg/day during organogenesis (Gestation Day [GD] 6 to GD15) in pregnant rats did not cause maternal or embryo-fetal toxicity at doses up to 1,000 mg/kg/day corresponding to maternal plasma exposures up to 7.3 times the estimated human exposure for the treatment of malaria based on AUC. In pregnant rabbits, atovaquone administered in oral doses of 300, 600, and 1,200 mg/kg/day by gavage during organogenesis (GD6 to GD18) was associated with decreased fetal body length at a maternally toxic dose of 1,200 mg/kg/day corresponding to plasma exposures that were approximately 1.3 times the estimated human exposure during treatment of malaria based on AUC. In a pre- and post-natal study in rats, atovaquone administered in oral doses of 250, 500, and 1,000 mg/kg/day from GD15 until Lactation Day (LD) 20 did not impair the growth or developmental effects in first generation offspring at doses up to 1,000 mg/kg/day corresponding to AUC exposures of approximately 7.3 times the estimated human exposure during treatment of malaria. Atovaquone crossed the placenta and was present in fetal rat and rabbit tissue. Proguanil Proguanil administered orally to pregnant rats during organogenesis (GD6 to GD17) was not associated with fetal malformations, but increased ureter variations at a maternally toxic dose of 20 mg/kg/day corresponding to a plasma concentration approximately equal to 0.07 times the estimated human exposure for the treatment of malaria based on AUC. Proguanil given orally by gavage at a maternally toxic dose of 40 mg/kg/day to pregnant rabbits during organogenesis (GD6 to GD20) did not produce adverse embryo-fetal effects at a plasma concentration up to 0.8 times the estimated human exposure for the treatment of malaria based on AUC. In a pre- and post-natal study in female rats, proguanil hydrochloride administered in oral doses of 4, 8, or 16 mg/kg/day from GD6 until LD20 did not impair the growth, development, or reproductive ability of first generation offspring or the survivability of second generation offspring at doses up to 16 mg/kg/day (0.04 times the average human exposure based on AUC). Pre- and post-natal studies of proguanil in animals at exposures similar to or greater than those observed in humans have not been conducted. Atovaquone and Proguanil The combination of atovaquone and proguanil hydrochloride administered orally to pregnant rats in atovaquone:proguanil hydrochloride doses of 12.5:5, 25:10, and 50:20 mg/kg/day during organogenesis (GD6 to GD17) did not produce maternal toxicity or adverse embryo-fetal developmental effects with doses up to 50:20 mg/kg/day corresponding to plasma concentrations up to 1.7 and 0.1 times, respectively, the estimated human exposure during treatment of malaria based on AUC. In pregnant rabbits, the combination of atovaquone and proguanil hydrochloride administered orally in atovaquone:proguanil hydrochloride doses of 25:10, 50:20, or 100:40 mg/kg/day during organogenesis (GD6 to GD20) did not produce adverse embryo-fetal developmental effects at a maternally toxic dose of 100:40 mg/kg/day corresponding to plasma concentrations of approximately 0.3 and 0.5 times, respectively, the estimated human exposure during treatment of malaria based on AUC. 8.2 Lactation Risk Summary There are no data on the presence of atovaquone in human milk; however, proguanil is present in human milk. Atovaquone is present in rat milk (see Data ) . When a drug is present in animal milk, it is likely the drug will be present in human milk. There are no data on the effects of atovaquone and proguanil on the breastfed child or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for atovaquone and proguanil hydrochloride tablets and any potential adverse effect on the breastfed child from atovaquone and proguanil or from the underlying maternal condition. Data In a rat study with doses of 10 and 250 mg/kg, given orally by gavage on postpartum Day 11, atovaquone concentrations in the milk were 30% of the concurrent atovaquone concentrations in the maternal plasma at both doses. The concentration of drug in animal milk does not necessarily predict the concentration of drug in human milk. 8.4 Pediatric Use Prophylaxis of Malaria Safety and effectiveness have not been established in pediatric patients who weigh less than 11 kg. The efficacy and safety of atovaquone and proguanil hydrochloride tablets have been established for the prophylaxis of malaria in controlled trials involving pediatric patients weighing 11 kg or more [see Clinical Studies (14.1) ] . Treatment of Malaria Safety and effectiveness have not been established in pediatric patients who weigh less than 5 kg. The efficacy and safety of atovaquone and proguanil hydrochloride tablets for the treatment of malaria have been established in controlled trials involving pediatric patients weighing 5 kg or more [see Clinical Studies (14.2) ] . 8.5 Geriatric Use Clinical trials of atovaquone and proguanil hydrochloride tablets did not include sufficient numbers of subjects aged 65 years and older to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, the higher systemic exposure to cycloguanil, and the greater frequency of concomitant disease or other drug therapy [see Clinical Pharmacology (12.3) ]. 8.6 Renal Impairment Do not use atovaquone and proguanil hydrochloride tablets for malaria prophylaxis in patients with severe renal impairment (creatinine clearance < 30 mL/min). Use with caution for the treatment of malaria in patients with severe renal impairment only if the benefits of the 3-day treatment regimen outweigh the potential risks associated with increased drug exposure. No dosage adjustments are needed in patients with mild (creatinine clearance 50 to 80 mL/min) or moderate (creatinine clearance 30 to 50 mL/min) renal impairment [see Clinical Pharmacology (12.3) ]. 8.7 Hepatic Impairment No dosage adjustments are needed in patients with mild or moderate hepatic impairment [see Clinical Pharmacology (12.3) ] . No trials have been conducted in patients with severe hepatic impairment.