Atovaquone/proguanil Disease Interactions

Atovaquone and Proguanil tablets are contraindicated for prophylaxis of P. falciparum malaria in patients with severe renal impairment (creatinine clearance <30 mL/min) because of pancytopenia in patients with severe renal impairment treated with proguanil. Use with caution for the treatment of malaria in patients with severe renal impairment, only if the benefits of the 3-day treatment regimen outweigh the potential risks associated with increased drug exposure. No dosage adjustments are needed in patients with mild (creatinine clearance 50 to 80 mL/min) or moderate (creatinine clearance 30 to 50 mL/min) renal impairment.

Oral bioavailability of atovaquone is limited under fasting conditions, but is increased approximately two-fold when administered with food. Patients with gastrointestinal disorders or eating difficulties may be more likely to have impaired absorption and, consequently, subtherapeutic levels of the drug. Alternative parenteral treatment should be considered for patients unable to achieve adequate plasma concentrations of atovaquone with oral administration.

Atovaquone may cause elevated liver function tests. In clinical trials, elevated serum alkaline phosphatase concentrations (> 2.5 times the upper limit of normal, or ULN) were reported in approximately 8% of patients, and elevations in serum ALT and AST (> 5 times ULN) were reported in 6% and 4% of patients, respectively. Increases in serum bilirubin has occurred rarely. Atovaquone also may undergo limited metabolism by the liver. Therapy with atovaquone should be administered cautiously in patients with severe hepatic impairment. Liver function tests should be performed periodically, and therapy withdrawn if significant elevations develop.

No proguanil dosage adjustments are needed in patients with mild or moderate hepatic impairment, however, no trials have been conducted in patients with severe hepatic impairment. Caution is advised, as elevated liver laboratory tests and cases of hepatitis and hepatic failure requiring liver transplantation have been reported with prophylactic use of atovaquone and proguanil hydrochloride tablets.