July 31, 2015
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Mepron

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Mepron




Warnings
Precautions

WARNINGS

Included as part of the PRECAUTIONSsection.

PRECAUTIONS

Risk Of Limited Oral Absorption

Absorption of orally administered MEPRON suspension is limited but can be significantly increased when the drug is taken with food. Failure to administer MEPRON suspension with food may result in lower plasma atovaquone concentrations and may limit response to therapy. Consider therapy with other agents in patients who have difficulty taking MEPRON suspension with food or in patients who have gastrointestinal disorders that may limit absorption of oral medications [see CLINICAL PHARMACOLOGY].

Hepatotoxicity

Cases of cholestatic hepatitis, elevated liver enzymes, and fatal liver failure have been reported in patients treated with atovaquone [see ADVERSE REACTIONS].

If treating patients with severe hepatic impairment, closely monitor patients following administration of MEPRON.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenicity studies in rats were negative; 24-month studies in mice (dosed with 50, 100, or 200 mg/kg/day), showed treatment-related increases in incidence of hepatocellular adenoma and hepatocellular carcinoma at all doses tested, which correlated with 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.

Use In Specific Populations

Pregnancy

Pregnancy Category C

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. 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 (dose of 1,000 mg/kg/day in rats). 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 (dose of 1,200 mg/kg/day in rabbits). 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 (1,000 mg/kg), concentrations of radiocarbon in rat fetuses were 18% (middle gestation) and 60% (late gestation) of concurrent maternal plasma concentrations.

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 (with doses of 10 and 250 mg/kg), atovaquone concentrations in the milk were 30% of the concurrent atovaquone concentrations in the maternal plasma at both doses.

Pediatric Use

Evidence of safety and effectiveness in pediatric patients (aged 12 years and younger) has not been established. In a trial of MEPRON suspension administered once daily with food for 12 days to 27 HIV-1-infected, asymptomatic infants and children aged between 1 month and 13 years, the pharmacokinetics of atovaquone were age-dependent. The average steady-state plasma atovaquone concentrations in the 24 subjects with available concentration data are shown in Table 5.

Table 5: Average Steady-state Plasma Atovaquone Concentrations in Pediatric Subjects

Age Dose of MEPRON Suspension
10 mg/kg 30 mg/kg 45 mg/kg
Average Css in mcg/mL (mean ± SD)
1-3 months 5.9
(n = 1)
27.8 ± 5.8
(n = 4)
> 3-24 months 5.7 ± 5.1
(n = 4)
9.8 ± 3.2
(n = 4)
15.4 ± 6.6
(n = 4)
> 2-13 years 16.8 ± 6.4
(n = 4)
37.1 ± 10.9
(n = 3)
_
Css = Concentration at steady state.

Geriatric Use

Clinical trials of MEPRON did not include sufficient numbers of subjects aged 65 years and older to determine whether they respond differently from younger subjects.

Last reviewed on RxList: 6/26/2015
This monograph has been modified to include the generic and brand name in many instances.

Warnings
Precautions

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