Atovaquone and Proguanil Hydrochloride (Page 2 of 6)

Special Populations:

Pediatrics:

The pharmacokinetics of proguanil and cycloguanil are similar in adult patients and pediatric patients. However, the elimination half-life of atovaquone is shorter in pediatric patients (1 to 2 days) than in adult patients (2 to 3 days). In clinical trials, plasma trough levels of atovaquone and proguanil in pediatric patients weighing 5 to 40 kg were within the range observed in adults after dosing by body weight.

Geriatrics:

In a single-dose study, the pharmacokinetics of atovaquone, proguanil, and cycloguanil were compared in 13 elderly subjects (age 65 to 79 years) to 13 younger subjects (age 30 to 45 years). In the elderly subjects, the extent of systemic exposure (AUC) of cycloguanil was increased (point estimate = 2.36, CI = 1.70, 3.28). Tmax was longer in elderly subjects (median 8 hours) compared with younger subjects (median 4 hours) and average elimination half-life was longer in elderly subjects (mean 14.9 hours) compared with younger subjects (mean 8.3 hours).

Hepatic Impairment:

In a single-dose study, the pharmacokinetics of atovaquone, proguanil, and cycloguanil were compared in 13 subjects with hepatic impairment (9 mild, 4 moderate, as indicated by the Child-Pugh method) to 13 subjects with normal hepatic function. In subjects with mild or moderate hepatic impairment as compared to healthy subjects, there were no marked differences (<50%) in the rate or extent of systemic exposure of atovaquone. However, in subjects with moderate hepatic impairment, the elimination half-life of atovaquone was increased (point estimate = 1.28, 90% CI = 1.00 to 1.63). Proguanil AUC, Cmax , and its t1/2 increased in subjects with mild hepatic impairment when compared to healthy subjects (Table 2). Also, the proguanil AUC and its t1/2 increased in subjects with moderate hepatic impairment when compared to healthy subjects. Consistent with the increase in proguanil AUC, there were marked decreases in the systemic exposure of cycloguanil (Cmax and AUC) and an increase in its elimination half-life in subjects with mild hepatic impairment when compared to healthy volunteers (Table 2). There were few measurable cycloguanil concentrations in subjects with moderate hepatic impairment (see DOSAGE AND ADMINISTRATION). The pharmacokinetics of atovaquone, proguanil, and cycloguanil after administration of a tovaquone and proguanil hydrochloride have not been studied in patients with severe hepatic impairment.

Table 2. Point Estimates (90% CI) for Proguanil and Cycloguanil Parameters in Subjects With Mild and Moderate Hepatic Impairment Compared to Healthy Volunteers
ND = not determined due to lack of quantifiable data.
*
Ratio of geometric means.
Mean difference.

Parameter

Comparison

Proguanil

Cycloguanil

AUC (0-inf)

mild : healthy

1.96 (1.51, 2.54)

0.32 (0.22, 0.45)

Cmax *

mild : healthy

1.41 (1.16, 1.71)

0.35 (0.24, 0.50)

T 1/2

mild : healthy

1.21 (0.92, 1.60)

0.86 (0.49, 1.48)

AUC (0-inf) *

moderate : healthy

1.64 (1.14, 2.34)

ND

Cmax *

moderate : healthy

0.97 (0.69, 1.36)

ND

T 1/2

moderate : healthy

1.46 (1.05, 2.05)

ND

Renal Impairment:

In patients with mild renal impairment (creatinine clearance 50 to 80 mL/min), oral clearance and/or AUC data for atovaquone, proguanil, and cycloguanil are within the range of values observed in patients with normal renal function (creatinine clearance >80 mL/min). In patients with moderate renal impairment (creatinine clearance 30 to 50 mL/min), mean oral clearance for proguanil was reduced by approximately 35% compared with patients with normal renal function (creatinine clearance >80 mL/min) and the oral clearance of atovaquone was comparable between patients with normal renal function and mild renal impairment. No data exist on the use of atovaquone and proguanil hydrochloride for long-term prophylaxis (over 2 months) in individuals with moderate renal failure. In patients with severe renal impairment (creatinine clearance <30 mL/min), atovaquone Cmax and AUC are reduced but the elimination half-lives for proguanil and cycloguanil are prolonged, with corresponding increases in AUC, resulting in the potential of drug accumulation and toxicity with repeated dosing (see CONTRAINDICATIONS).

Drug Interactions:

There are no pharmacokinetic interactions between atovaquone and proguanil at the recommended dose.

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

Concomitant treatment with metoclopramide has also been associated with decreased bioavailability of atovaquone.

Concomitant administration of rifampin or rifabutin is known to reduce atovaquone levels by approximately 50% and 34%, respectively (see PRECAUTIONS: Drug Interactions). The mechanisms of these interactions are unknown.

Concomitant administration of atovaquone (750 mg BID with food for 14 days) and indinavir (800 mg TID 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%]). Caution should be exercised when prescribing atovaquone with indinavir due to the decrease in trough levels of indinavir.

Atovaquone is highly protein bound (>99%) but does not displace other highly protein-bound drugs in vitro, indicating significant drug interactions arising from displacement are unlikely (see PRECAUTIONS: Drug Interactions). Proguanil is metabolized primarily by CYP2C19. Potential pharmacokinetic interactions with other substrates or inhibitors of this pathway are unknown.

INDICATIONS AND USAGE

Prevention of Malaria:

Atovaquone and proguanil hydrochloride tablets are indicated for the prophylaxis of P. falciparum malaria, including in areas where chloroquine resistance has been reported (see CLINICAL STUDIES).

Treatment of Malaria:

Atovaquone and proguanil hydrochloride tablets are indicated for the treatment of acute, uncomplicated P. falciparum malaria. Atovaquone and proguanil hydrochloride tablets have been shown to be effective in regions where the drugs chloroquine, halofantrine, mefloquine, and amodiaquine may have unacceptable failure rates, presumably due to drug resistance.

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