Atovaquone (Page 2 of 6)

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of atovaquone oral suspension. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Blood and Lymphatic System Disorders: Methemoglobinemia, thrombocytopenia.

Immune System Disorders: Hypersensitivity reactions including angioedema, bronchospasm, throat tightness, and urticaria.

Eye Disorders: Vortex keratopathy.

Gastrointestinal Disorders: Pancreatitis.

Hepatobiliary Disorders: Hepatitis, fatal liver failure.

Skin and Subcutaneous Tissue Disorders: Erythema multiforme, Stevens-Johnson syndrome, and skin desquamation.

Renal and Urinary Disorders: Acute renal impairment.

7 DRUG INTERACTIONS

7.1 Rifampin/Rifabutin

Concomitant administration of rifampin or rifabutin and atovaquone oral suspension is known to reduce atovaquone concentrations [see CLINICAL PHARMACOLOGY (12.3)] . Concomitant administration of atovaquone oral suspension and rifampin or rifabutin is not recommended.

7.2 Tetracycline

Concomitant administration of tetracycline and atovaquone oral suspension has been associated with a reduction in plasma concentrations of atovaquone [see CLINICAL PHARMACOLOGY (12.3)]. Caution should be used when prescribing tetracycline concomitantly with atovaquone oral suspension. Monitor patients for potential loss of efficacy of atovaquone if coadministration is necessary.

7.3 Metoclopramide

Metoclopramide may reduce the bioavailability of atovaquone and should be used only if other antiemetics are not available [see CLINICAL PHARMACOLOGY (12.3)].

7.4 Indinavir

Concomitant administration of atovaquone and indinavir did not result in any change in the steady-state AUC and C max of indinavir but resulted in a decrease in the C trough of indinavir [see CLINICAL PHARMACOLOGY (12.3)]. Caution should be exercised when prescribing atovaquone oral suspension with indinavir due to the decrease in trough concentrations of indinavir. Monitor patients for potential loss of efficacy of indinavir if coadministration with atovaquone oral suspension is necessary.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Available data from postmarketing experience with use of atovaquone in pregnant women are insufficient to identify a drug-associated risk for major birth defects, miscarriage, or adverse maternal or fetal outcomes. Pregnant women with HIV who are infected with PCP are at increased risk of adverse pregnancy outcomes (see Clinical Considerations) . Atovaquone given orally by gavage to pregnant rats and rabbits during organogenesis did not cause fetal malformations at plasma concentrations up to 3 times and 0.5 times, respectively, the estimated human exposure based on steady-state plasma concentrations (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: Pregnant women with HIV who are infected with PCP are at increased risk of severe illness and maternal death associated with PCP compared with non-pregnant women.

Data

Animal Data:

Atovaquone administered in oral doses of 250, 500, and 1,000 mg/kg/day to pregnant rats during organogenesis (Gestation Day [GD] 6 to GD15) did not cause maternal or embryo-fetal toxicity at doses up to 1,000 mg/kg/day corresponding to maternal plasma concentrations approximately 3 times the estimated human exposure during the treatment of PCP based on steady-state plasma concentrations. In pregnant rabbits, atovaquone administered in oral doses of 300, 600, and 1,200 mg/kg/day during organogenesis (GD6 to GD18) caused decreased fetal body length at a maternally toxic dose of 1,200 mg/kg/day corresponding to a plasma concentration that is approximately 0.5 times the estimated human exposure based on steady-state plasma concentrations. 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 approximately 3 times the estimated human exposure based on steady-state plasma concentrations during the treatment of PCP. Atovaquone crossed the placenta and was present in fetal rat and rabbit tissue.

8.2 Lactation

Risk Summary

The Centers for Disease Control and Prevention recommend that HIV-1-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV-1. There are no data on the presence of atovaquone in human milk, the effects on the breastfed child, or the effects on milk production.

Atovaquone was detected in rat milk when lactating rats were administered oral atovaquone (see Data) . When a drug is present in animal milk, it is likely the drug will be present in human milk. Because of the potential for HIV-1 transmission to HIV-negative infants, instruct mothers with HIV-1 not to breastfeed if they are taking atovaquone for the prevention or treatment of PCP.

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.

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