Atovaquone and Proguanil Hydrochloride (Page 2 of 6)

6.2 Postmarketing Experience

In addition to adverse events reported from clinical trials, the following events have been identified during postmarketing use of atovaquone and proguanil hydrochloride. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to atovaquone and proguanil hydrochloride.

Blood and Lymphatic System Disorders:

Neutropenia and anemia. Pancytopenia in patients with severe renal impairment treated with proguanil [see Contraindications (4)].

Immune System Disorders:

Allergic reactions including anaphylaxis, angioedema, and urticaria, and vasculitis.

Nervous System Disorders:

Seizures and psychotic events (such as hallucinations); however, a causal relationship has not been established.

Gastrointestinal Disorders:

Stomatitis.

Hepatobiliary Disorders:

Elevated liver laboratory tests, hepatitis, cholestasis; hepatic failure requiring transplant has been reported.

Skin and Subcutaneous Tissue Disorders:

Photosensitivity, rash, erythema multiforme, and Stevens-Johnson syndrome

7 DRUG INTERACTIONS

7.1 Rifampin/Rifabutin

Concomitant administration of rifampin or rifabutin is known to reduce atovaquone concentrations [see Clinical Pharmacology (12.3)]. The concomitant administration of atovaquone and proguanil hydrochloride and rifampin or rifabutin is not recommended.

7.2 Anticoagulants

Proguanil may potentiate the anticoagulant effect of warfarin and other coumarin-based anticoagulants. The mechanism of this potential drug interaction has not been established. Caution is advised when initiating or withdrawing malaria prophylaxis or treatment with atovaquone and proguanil hydrochloride in patients on continuous treatment with coumarin-based anticoagulants. When these products are administered concomitantly, coagulation tests should be closely monitored.

7.3 Tetracycline

Concomitant treatment with tetracycline has been associated with a reduction in plasma concentrations of atovaquone [see Clinical Pharmacology (12.3)]. Parasitemia should be closely monitored in patients receiving tetracycline.

7.4 Metoclopramide

While antiemetics may be indicated for patients receiving atovaquone and proguanil hydrochloride, metoclopramide may reduce the bioavailability of atovaquone and should be used only if other antiemetics are not available [see Clinical Pharmacology (12.3)].

7.5 Indinavir

Concomitant administration of atovaquone and indinavir did not result in any change in the steady-state AUC and Cmax of indinavir but resulted in a decrease in the Ctrough of indinavir [see Clinical Pharmacology (12.3)]. Caution should be exercised when prescribing atovaquone with indinavir due to the decrease in trough concentrations of indinavir

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Available data for published literature and postmarketing experience with the use of atovaquone and proguanil hydrochloride 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 indicates population in 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 plasmas exposures that were approximately 1.3 times the estimated human exposure during treatment of malaria based on AUC. In a pre- and pot-natal study in rats, atovaquone administered in oral doses of 250, 500 and 1,000 mg/day/day form GD15 until Lactation Day (LD) 20 did not impair the growth or development effects in the first generation offspring at dosed 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, of 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 concentration of approximately 0.3 and 0.5 times, respectively, the estimated human exposure during treatment of malaria based on AUC.

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