Atovaquone (Page 3 of 5)

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.


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.


Atovaquone Oral Suspension, USP is a quinone antimicrobial drug. The chemical name of atovaquone USP is trans -2-[4-(4-chlorophenyl) cyclohexyl]-3-hydroxy-1,4-naphthalenedione. Atovaquone USP is a yellow crystalline powder that is freely soluble in N-methyl-2-pyrrolidone and in tetrahydrofuran; soluble in chloroform; sparingly soluble in acetone and dimethyl sulfoxide; slightly soluble in octanol, ethyl acetate and polyethylene glycol 200; very slightly soluble in 0.1N sodium hydroxide; insoluble in water. It has a molecular weight of 366.84 g/mol and the molecular formula C22 H19 ClO3 . The compound has the following structural formula:

(click image for full-size original)

Atovaquone Oral Suspension, USP is a formulation of micro-fine particles of atovaquone USP.

Each 5 mL of Atovaquone Oral Suspension, USP contains 750 mg of atovaquone USP and the inactive ingredients benzyl alcohol, citric acid monohydrate, hypromellose, poloxamer 188, purified water, saccharin sodium, trisodium citrate dihydrate, tutti frutti flavor and xanthan gum.


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 Treatmenta No. of Successes/ No. in Group

0 to <5

0/6 (0%)

5 to <10

18/26 (69%)

10 to <15

30/38 (79%)

15 to <20

18/19 (95%)


24/24 (100%)

a 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.

Cardiac Effects

The effect of atovaquone oral suspension on the QT interval is unknown in humans.

12.3 Pharmacokinetics

Plasma atovaquone concentrations do not increase proportionally with dose following ascending repeat-dose administration of atovaquone oral suspension in healthy subjects. When atovaquone oral suspension was administered with food at dosage regimens of 500 mg once daily, 750 mg once daily, and 1,000 mg once daily, mean (±SD) steady-state plasma atovaquone concentrations were 11.7 ± 4.8, 12.5 ± 5.8, and 13.5 ± 5.1 mcg/mL, respectively. The corresponding mean (±SD) Cmax concentrations were 15.1 ± 6.1, 15.3 ± 7.6, and 16.8 ± 6.4 mcg/mL.


Atovaquone is a highly lipophilic compound with low aqueous solubility. The mean (±SD) absolute bioavailability of atovaquone from a 750-mg dose of atovaquone oral suspension administered under fed conditions in 9 HIV-1-infected (CD4 >100 cells/mm3) volunteers was 47% ± 15%.

Effect of Food: Administering atovaquone oral suspension with food enhances atovaquone bioavailability. Sixteen healthy subjects received a single 750 mg- dose of atovaquone oral suspension after an overnight fast and following a meal (23 g fat: 610 kCal). The mean (SD) atovaquone AUC under fasting and fed conditions were 324  115 and 801  320 h●mcg/mL, respectively, representing a 2.6  1-fold increase.


Following IV administration of atovaquone, the mean (±SD) volume of distribution at steady state (Vdss ) was 0.60 ± 0.17 L/kg (n = 9). Atovaquone is extensively bound to plasma proteins (99.9%) over the concentration range of 1 to 90 mcg/mL. In 3 HIV-1-infected children who received 750 mg atovaquone as the tablet formulation 4 times daily for 2 weeks, the cerebrospinal fluid concentrations of atovaquone were 0.04, 0.14, and 0.26 mcg/mL, representing less than 1% of the plasma concentration.


The mean (SD) half-life of atovaquone was 62.5  35.3 hours after IV administration and ranged from 67  33.4 to 77.6  23.1 hours following administration of atovaquone oral suspension.

Metabolism: The metabolism of atovaquone is unknown.

Excretion: Following oral administration of 14 C-labelled atovaquone was administered to healthy subjects, greater than 94% of the dose was recovered as unchanged atovaquone in the feces over 21 days.

Specific Populations

Patients with Hepatic or Renal Impairment: The pharmacokinetics of atovaquone have not been studied in patients with hepatic or renal impairment.

HIV-Infected Subjects: When atovaquone oral suspension was administered to 5 HIV-1–infected subjects at a dose of 750 mg twice daily, the mean (±SD) steady-state plasma atovaquone concentration was 21 ± 4.9 mcg/mL and mean (±SD) Cmax was 24 ± 5.7 mcg/mL. The mean (±SD) minimum plasma atovaquone concentration (Cmin ) associated with the 750-mg twice-daily regimen was 16.7 ± 4.6 mcg/mL.

In an open-label PCP trial in 18 HIV-1–infected subjects, administration of atovaquone oral suspension 750 mg twice daily with meals resulted in a mean (±SD) steady-state plasma atovaquone concentration of 22 ± 10.1 mcg/mL.

The mean (±SD) plasma clearance of atovaquone following IV administration in 9 HIV-1–infected subjects was 10.4 ± 5.5 mL/min (0.15 ± 0.09 mL/min/kg).

Drug Interaction Studies

Rifampin/Rifabutin: In a trial with 13 HIV-1-infected volunteers, the oral administration of rifampin 600 mg every 24 hours with atovaquone oral suspension 750 mg every 12 hours resulted in a 52% ± 13% decrease in the mean (±SD) steady‑state plasma atovaquone concentration and a 37% ± 42% increase in the mean (±SD) steady‑state plasma rifampin concentration. The half‑life of atovaquone decreased from 82 ± 36 hours when administered without rifampin to 50 ± 16 hours with rifampin. In a trial of 24 healthy volunteers, the oral administration of rifabutin 300 mg once daily with atovaquone oral suspension 750 mg twice daily resulted in a 34% decrease in the mean steady‑state plasma atovaquone concentration and a 19% decrease in the mean steady‑state plasma rifabutin concentration.

Tetracycline: Concomitant treatment with tetracycline has been associated with a 40% reduction in plasma concentrations of atovaquone.

Metoclopramide: Concomitant treatment with metoclopramide has been associated with a 50% reduction in steady-state atovaquone plasma concentrations.

Indinavir: Concomitant administration of atovaquone (750 mg twice daily with food for 14 days) and indinavir (800 mg three times daily without food for 14 days) 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 (23% decrease [90% CI: 8%, 35%]).

Trimethoprim/Sulfamethoxazole: Concomitant administration of atovaquone oral suspension 500 mg once daily (not the approved dosage) and TMP-SMX in 6 HIV-infected adult subjects did not result in significant changes in either atovaquone or TMP-SMX exposure.

Zidovudine: The administration of atovaquone tablets 750 mg every 12 hours with zidovudine 200 mg every 8 hours to 14 HIV-1 infected subjects resulted in a 24% ± 12% decrease in zidovudine apparent oral clearance, leading to a 35% ± 23% increase in plasma zidovudine AUC. The glucuronide metabolite: parent ratio decreased from a mean of 4.5 when zidovudine was administered alone to 3.1 when zidovudine was administered with atovaquone tablets. This effect is minor and would not be expected to produce clinically significant events. Zidovudine had no effect on atovaquone pharmacokinetics.

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