Atovaquone (Page 4 of 8)

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

Evidence of safety and effectiveness in pediatric patients (aged 12 years and younger) has not been established. In a trial of atovaquone oral 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 Atovaquone Oral Suspension
10 mg/kg 30 mg/kg 45 mg/kg
Average Css in mcg/mL (mean ± SD)
Css = Concentration at steady state.
1 to 3 months 5.9 (n = 1) 27.8 ± 5.8 (n = 4)
>3 to 24 months 5.7 ± 5.1 (n = 4) 9.8 ± 3.2 (n = 4) 15.4 ± 6.6 (n = 4)
>2 to13 years 16.8 ± 6.4 (n = 4) 37.1 ± 10.9 (n = 3)

8.5 Geriatric Use

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

10 OVERDOSAGE

Overdoses up to 31,500 mg of atovaquone have been reported. In one such patient who also took an unspecified dose of dapsone, methemoglobinemia occurred. Rash has also been reported after overdose. There is no known antidote for atovaquone, and it is currently unknown if atovaquone is dialyzable.

11 DESCRIPTION

Atovaquone oral solution is a quinone antimicrobial drug. The chemical name of atovaquone is trans -2-[4-(4- chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthalenedione. Atovaquone is a yellow crystalline solid that is practically insoluble in water. It has a molecular weight of 366.84 and the molecular formula C 22 H 19 ClO 3 . The compound has the following structural formula:

Chemical Structure
(click image for full-size original)

Atovaquone oral suspension is a formulation of micro-fine particles of atovaquone.

Each 5 mL of atovaquone oral suspension, USP contains 750 mg of atovaquone and the inactive ingredients benzyl alcohol, flavor, hypromellose poloxamer, purified water, saccharin sodium, and xanthan gum.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Atovaquone is a quinone antimicrobial drug [see Microbiology (12.4)] .

12.2 Pharmacodynamics

Relationship between Plasma Atovaquone Concentrations and Clinical Outcome

In a comparative clinical trial, HIV/AIDS subjects received atovaquone tablets 750 mg 3 times daily or TMP-SMX for treatment of mild-to-moderate PCP for 21 days [see CLINICAL STUDIES (14.2)] ; the relationship between atovaquone plasma concentrations and successful treatment outcome from 113 of these subjects for whom both steady-state drug concentrations and outcome data were available is shown in Table 6.

Table 6. Relationship between Plasma Atovaquone Concentrations and Successful Treatment Outcome
Steady-State Plasma Atovaquone Concentrations (mcg/mL) Successful Treatment *No. of Successes/No. in Group (%)
*
Successful treatment outcome was defined as improvement in clinical and respiratory measures persisting at least 4 weeks after cessation of therapy. Improvement in clinical and respiratory measures was assessed using a composite of parameters that included oral body temperature, respiratory rate, and severity scores for cough, dyspnea, and chest pain/tightness.
0 to <5 0/6 (0%)
5 to <10 18/26 (69%)
10 to <15 30/38 (79%)
15 to <20 18/19 (95%)
≥20 24/24 (100%)

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