Atovaquone warnings and precautions

# Warnings
Clinical experience with MEPRON for the treatment of PCP has been limited to patients with mild-to-moderate PCP (1 45 mm Hg). Treatment of more severe episodes of PCP has not been systematically studied with this agent. Also, the efficacy of MEPRON in patients who are failing therapy with TMP-SMX has not been systematically studied.

# Precautions

### General
Absorption of orally administered MEPRON is limited but can be significantly increased when the drug is taken with food. Plasma atovaquone concentrations have been shown to correlate with the likelihood of successful treatment and survival. Therefore, parenteral therapy with other agents should be considered for patients who have difficulty taking MEPRON with food (see CLINICAL PHARMACOLOGY). Gastrointestinal disorders may limit absorption of orally administered drugs. Patients with these disorders also may not achieve plasma concentrations of atovaquone associated with response to therapy in controlled trials.
Based upon the spectrum of in vitro antimicrobial activity, atovaquone is not effective therapy for concurrent pulmonary conditions such as bacterial, viral, or other fungal pneumonia or mycobacterial diseases. Clinical deterioration in patients may be due to infections with other pathogens, as well as progressive PCP. All patients with acute PCP should be carefully evaluated for other possible causes of pulmonary disease and treated with additional agents as appropriate.
Rare cases of hepatitis, elevated liver function tests and one case of fatal liver failure have been reported in patients treated with atovaquone. A causal relationship between atovaquone use and these events could not be established because of numerous confounding medical conditions and concomitant drug therapies. (See ADVERSE REACTIONS.)
If it is necessary to treat patients with severe hepatic impairment, caution is advised and administration should be closely monitored.

### Information for Patients
The importance of taking the prescribed dose of MEPRON should be stressed. Patients should be instructed to take their daily doses of MEPRON with meals, as the presence of food will significantly improve the absorption of the drug.

## =Drug Interactions
Atovaquone is highly bound to plasma protein (>99.9%). Therefore, caution should be used when administering MEPRON concurrently with other highly plasma protein-bound drugs with narrow therapeutic indices, as competition for binding sites may occur. The extent of plasma protein binding of atovaquone in human plasma is not affected by the presence of therapeutic concentrations of phenytoin (15 mcg/mL), nor is the binding of phenytoin affected by the presence of atovaquone.
Coadministration of rifampin and MEPRON Suspension results in a significant decrease in average steady-state plasma atovaquone concentrations (see CLINICAL PHARMACOLOGY: Drug Interactions). Alternatives to rifampin should be considered during the course of PCP treatment with MEPRON.
Rifabutin, another rifamycin, is structurally similar to rifampin and may possibly have some of the same drug interactions as rifampin. No interaction trials have been conducted with MEPRON and rifabutin.

### Drug/Laboratory Test Interactions
It is not known if MEPRON interferes with clinical laboratory test or assay results.

### Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity studies in rats were negative; 24-month studies in mice showed treatment-related increases in incidence of hepatocellular adenoma and hepatocellular carcinoma at all doses tested which ranged from 1.4 to 3.6 times the average steady-state plasma concentrations in humans during acute treatment of PCP. Atovaquone was negative with or without metabolic activation in the Ames Salmonella mutagenicity assay, the Mouse Lymphoma mutagenesis assay, and the Cultured Human Lymphocyte cytogenetic assay. No evidence of genotoxicity was observed in the in vivo Mouse Micronucleus assay.

### Pregnancy Category: C
Atovaquone was not teratogenic and did not cause reproductive toxicity in rats at plasma concentrations up to 2 to 3 times the estimated human exposure. Atovaquone caused maternal toxicity in rabbits at plasma concentrations that were approximately one half the estimated human exposure. Mean fetal body lengths and weights were decreased and there were higher numbers of early resorption and post-implantation loss per dam. It is not clear whether these effects were caused by atovaquone directly or were secondary to maternal toxicity. Concentrations of atovaquone in rabbit fetuses averaged 30% of the concurrent maternal plasma concentrations. In a separate study in rats given a single 14C-radiolabelled dose, concentrations of radiocarbon in rat fetuses were 18% (middle gestation) and 60% (late gestation) of concurrent maternal plasma concentrations. There are no adequate and well-controlled studies in pregnant women. MEPRON should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

### Nursing Mothers
It is not known whether atovaquone is excreted into human milk. Because many drugs are excreted into human milk, caution should be exercised when MEPRON is administered to a nursing woman. In a rat study, atovaquone concentrations in the milk were 30% of the concurrent atovaquone concentrations in the maternal plasma.

### Pediatric Use
Evidence of safety and effectiveness in pediatric patients has not been established. A relationship between plasma atovaquone concentrations and successful treatment of PCP has been established in adults (see Table 2). In a study of MEPRON Suspension in 27 HIV-infected, asymptomatic infants and children between 1 month and 13 years of age, the pharmacokinetics of atovaquone were age-dependent (see CLINICAL PHARMACOLOGY: Special Populations). No drug-related treatment-limiting adverse events were observed in the pharmacokinetic study.

### Geriatric Use
Clinical studies of MEPRON did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.