AHFS Class:

• Antiprotozoals, Pneumocystis jirovecii Pneumonia 8:30.12

Generic Name(s):

• Atovaquone

Atovaquone, a synthetic hydroxynaphthoquinone derivative, is an antiprotozoal agent.1,7,8,10,15,17

Pneumocystis jirovecii Pneumonia

Atovaquone is used as an alternative for treatment of Pneumocystis jirovecii (formerly Pneumocystis carinii ) pneumonia (PCP) and prevention of P. jirovecii infections in patients who cannot tolerate co-trimoxazole.1,24,34,134,155,156 Atovaquone is designated an orphan drug by the US Food and Drug Administration (FDA) for treatment of PCP associated with acquired immunodeficiency syndrome (AIDS) and prevention of PCP in high-risk patients with human immunodeficiency virus (HIV) infection (i.e., history of one or more episodes of PCP and/or CD4⁺ T-cell counts of 200/mm² or lower).22

Treatment of Pneumocystis jirovecii Pneumonia

Atovaquone is used alone as an alternative for treatment of mild to moderate PCP in patients who cannot tolerate co-trimoxazole, including HIV-infected adults, adolescents, and children†.1,24,34,134,155,156 The manufacturer states that clinical experience with atovaquone has been limited to patients with mild to moderate PCP, and use of the drug for treatment of more severe PCP has not been systematically studied.1

Co-trimoxazole is the drug of choice for treatment of mild, moderate, or severe PCP, including PCP in HIV-infected adults, adolescents, and children.134,155,156

The US Centers for Disease Control and Prevention (CDC), National Institutes of Health (NIH), and Infectious Diseases Society of America (IDSA) state that alternative regimens for treatment of mild to moderate PCP in HIV-infected adults and adolescents when co-trimoxazole cannot be used are dapsone in conjunction with trimethoprim, primaquine in conjunction with clindamycin, or atovaquone alone.155 These experts state that atovaquone may be less effective than co-trimoxazole for treatment of mild to moderate PCP, but has fewer adverse effects.155 Although efficacy and safety of atovaquone have not been established in pediatric patients1 and data are limited regarding use of the drug for treatment of PCP in children, CDC, NIH, IDSA, and the American Academy of Pediatrics (AAP) state that the drug also can be considered an alternative for treatment of mild to moderate PCP in HIV-infected children when co-trimoxazole cannot be used.156 Atovaquone is not included in CDC, NIH, IDSA, and AAP recommendations for treatment of severe PCP.155,156

The indication for use of atovaquone for treatment of mild to moderate PCP is based on data from 2 randomized studies that evaluated efficacy and safety of atovaquone tablets (no longer commercially available in the US) compared with oral co-trimoxazole or IV pentamidine in patients with AIDS1,4,24 and results of comparative pharmacokinetic studies of atovaquone oral suspension and the previously available tablets.1 Mild to moderate PCP was manifested in these patients by an alveolar-arterial oxygen gradient (P_{A- aD}) of 45 mm Hg or less and an arterial oxygen pressure (PaO₂) on room air of 60 mm Hg or greater.1,24

In the study evaluating comparative efficacy and safety of atovaquone tablets (750 mg 3 times daily for 21 days) or co-trimoxazole (320 mg of trimethoprim [as co-trimoxazole] 3 times daily for 21 days), improvement in clinical and respiratory measures that persisted for at least 4 weeks after discontinuance of treatment was observed in 62 or 64% of patients receiving atovaquone or co-trimoxazole, respectively.1 While adverse effects were substantially less likely in atovaquone-treated patients, results of this study suggest that failure to respond by day 21 of treatment was more likely in those treated with atovaquone (17%) than in those treated with co-trimoxazole (6%).1,23,24 Mortality rate (intent-to-treat analysis) also was higher in those treated with atovaquone (8%) than in those treated with co-trimoxazole (3.4%).1,24 In addition, while most fatalities in atovaquone-treated patients resulted from combined pneumocystis and bacterial infections, bacterial infections did not contribute to death in those receiving co-trimoxazole.1,24

In the study evaluating comparative efficacy and safety of atovaquone tablets (750 mg 3 times daily for 21 days) or pentamidine (3-4 mg/kg given by single IV infusion daily for 21 days) in patients with mild to moderate PCP who could not tolerate co-trimoxazole or sulfonamides, improvement in clinical and respiratory measures that persisted for at least 4 weeks after discontinuance of treatment was observed in 57 or 40% of patients receiving atovaquone or pentamidine, respectively.1 In this study, failure to respond was more likely in those treated with atovaquone (29%) than in those treated with pentamidine (17%), but adverse effects were less likely with atovaquone (63%) than with pentamidine (72%).1 Mortality rates were similar (about 14%) in atovaquone- and pentamidine-treated patients.1

In both comparative studies, there was a correlation between death and plasma atovaquone concentrations.1 Patients with lower plasma atovaquone concentrations (e.g., less than 5 mcg/mL on day 4 of treatment) were more likely to die while receiving the drug.1

Prevention of Pneumocystis jirovecii Infections

Atovaquone is used alone or in conjunction with pyrimethamine (and leucovorin) as an alternative for prevention of P. jirovecii infections in HIV-infected adults, adolescents, and children† who cannot tolerate co-trimoxazole.1,33,38,134,155,156

The indication for use of atovaquone for prevention of PCP is based on data from 2 randomized, open-label studies that evaluated efficacy and safety of atovaquone oral suspension compared with either oral dapsone or aerosolized pentamidine in HIV-infected adults and adolescents at risk for PCP (i.e., CD4⁺ T-cell counts less than 200/mm² or a prior episode of PCP).1,33,38 Results of the study comparing atovaquone (1.5 g once daily) and dapsone (100 mg once daily) indicated that both regimens were similarly effective for prevention of PCP (median duration of follow-up 24 months); this finding was consistent for patients receiving prophylaxis to prevent initial episodes of PCP (primary prophylaxis) and those receiving secondary prophylaxis to prevent recurrence.1,33 Results of the study comparing atovaquone oral suspension (750 mg or 1.5 g once daily) and aerosolized pentamidine (300 mg once monthly) indicated that both regimens were similarly effective for prevention of PCP (median duration of follow-up 11.3 months).1,38 There were no clinically important differences in mortality rates among any of the treatment groups.1

Prevention of Initial Episode (Primary Prophylaxis)

CDC, NIH, and IDSA recommend that primary prophylaxis to prevent initial episodes of PCP be initiated in HIV-infected adults and adolescents with CD4⁺ T-cell counts less than 200/mm³ or a history of oropharyngeal candidiasis.155 These experts state that primary PCP prophylaxis should be considered in HIV-infected adults and adolescents with CD4⁺ T-cell percentages less than 14% or a history of an AIDS-defining illness who would not otherwise qualify for prophylaxis and also should be considered in those with CD4⁺ T-cell counts greater than 200 but less than 250/ mm³ if frequent monitoring of CD4⁺ T-cell counts (e.g., every 3 months) is not possible.155

CDC, NIH, and IDSA state that primary PCP prophylaxis should be discontinued in HIV-infected adults and adolescents who have responded to antiretroviral therapy and have CD4⁺ T-cell counts that have remained greater than 200/mm³ for longer than 3 months.155 Discontinuance of primary PCP prophylaxis is recommended in these individuals since it appears to add little benefit in terms of disease prevention (PCP, toxoplasmosis, bacterial infections) and discontinuance reduces the medication burden, cost, and potential for drug toxicity, drug interactions, and selection of drug-resistant pathogens.155 Primary PCP prophylaxis should be reinitiated if CD4⁺ T-cell counts decrease to less than 200/mm³.155

Co-trimoxazole is the drug of choice for primary PCP prophylaxis in HIV-infected adults and adolescents.155 CDC, NIH, and IDSA recommend that co-trimoxazole prophylaxis be continued, if clinically feasible, in individuals who experience adverse reactions to the drug that are not life-threatening; however, co-trimoxazole prophylaxis should be permanently discontinued and an alternative used in those with life-threatening adverse reactions to the drug.155

Alternative regimens recommended by CDC, NIH, and IDSA for primary PCP prophylaxis in HIV-infected adults and adolescents who cannot tolerate co-trimoxazole are dapsone alone, dapsone in conjunction with pyrimethamine (and leucovorin), aerosolized pentamidine, atovaquone alone, or atovaquone in conjunction with pyrimethamine (and leucovorin).155 In HIV-infected adults or adolescents who cannot tolerate co-trimoxazole and are seropositive for Toxoplasma gondii , dapsone with pyrimethamine (and leucovorin), atovaquone alone, or atovaquone with pyrimethamine (and leucovorin) would provide prophylaxis against both PCP and toxoplasmosis.155

Prevention of Recurrence (Secondary Prophylaxis)

CDC, NIH, and IDSA recommend that HIV-infected adults and adolescents who have a history of PCP receive long-term suppressive or chronic maintenance therapy (secondary prophylaxis) to prevent recurrence.155

Secondary PCP prophylaxis generally is administered for life, unless immune recovery occurs as a result of antiretroviral therapy.155 CDC, NIH, and IDSA state that secondary PCP prophylaxis generally can be discontinued in HIV-infected adults and adolescents who have responded to antiretroviral therapy and have CD4⁺ T-cell counts that have remained greater than 200/mm³ for longer than 3 months, but should be reinitiated if CD4⁺ T-cell counts decrease to less than 200/mm³.155 In addition, these experts state that it may be prudent to continue secondary PCP prophylaxis for life (regardless of CD4⁺ T-cell count) if PCP occurred or recurred when CD4⁺ T-cell counts were greater than 200/mm³.155

Co-trimoxazole is the drug of choice for secondary PCP prophylaxis in HIV-infected adults and adolescents.155 CDC, NIH, and IDSA recommend that co-trimoxazole prophylaxis be continued, if clinically feasible, in individuals who experience adverse reactions to the drug that are not life-threatening; however, co-trimoxazole prophylaxis should be permanently discontinued and an alternative used in those with life-threatening adverse reactions to the drug.155

Alternative regimens recommended by CDC, NIH, and IDSA for secondary PCP prophylaxis in HIV-infected adults and adolescents who cannot tolerate co-trimoxazole are the same as those recommended for primary prophylaxis and include dapsone alone, dapsone in conjunction with pyrimethamine (and leucovorin), aerosolized pentamidine, atovaquone alone, or atovaquone in conjunction with pyrimethamine (and leucovorin).155 In HIV-infected adults or adolescents who cannot tolerate co-trimoxazole and are seropositive for T. gondii , dapsone with pyrimethamine (and leucovorin), atovaquone alone, or atovaquone with pyrimethamine (and leucovorin) would provide prophylaxis against both PCP and toxoplasmosis.155

Primary and Secondary Prophylaxis in Children

CDC, NIH, IDSA, and AAP recommend that primary prophylaxis to prevent initial episodes of PCP be initiated in HIV-infected children 1 to less than 6 years of age with CD4⁺ T-cell counts less than 500/mm³ or CD4⁺ T-cell percentages less than 15% and in HIV-infected children 6-12 years of age with CD4⁺ T-cell counts less than 200/mm³ or CD4⁺ T-cell percentages less than 15%.156 These experts recommend that all HIV-infected infants younger than 1 year of age (regardless of CD4⁺ T-cell count or percentage) receive primary PCP prophylaxis.156 In addition, infants born to HIV-infected mothers should be considered for primary PCP prophylaxis beginning at 4-6 weeks of age and those with indeterminate HIV status should continue to receive prophylaxis until they are determined to be non-HIV-infected or presumptively non-HIV-infected.156 Those found to be HIV-infected should receive primary PCP prophylaxis throughout the first year of life; at 1 year of age, the need for continued PCP prophylaxis should be reassessed based on age-specific CD4⁺ T-cell thresholds.156

HIV-infected children who have a history of PCP should receive long-term suppressive or chronic maintenance therapy (secondary prophylaxis) to prevent recurrence.156

CDC, NIH, IDSA, and AAP state that, in HIV-infected children who have received at least 6 months of antiretroviral therapy, discontinuance of primary or secondary PCP prophylaxis should be considered in those 1 to less than 6 years of age if CD4⁺ T-cell counts have remained at 500/mm³ or greater or CD4⁺ T-cell percentages have remained at 15% or greater for more than 3 consecutive months and in those 6-12 years of age if CD4⁺ T-cell counts have remained at 200/mm³ or greater or CD4⁺ T-cell percentages have remained at 15% or greater for more than 3 consecutive months.156 If primary or secondary PCP prophylaxis is discontinued in HIV-infected children, CD4⁺ T-cell counts and CD4⁺ T-cell percentages should be assessed every 3 months and PCP prophylaxis reinitiated if indicated based on age-specific CD4⁺ T-cell thresholds.156

Co-trimoxazole is the drug of choice for primary and secondary PCP prophylaxis in HIV-infected infants and children.156 CDC, NIH, IDSA, and AAP recommend that co-trimoxazole be continued, if clinically feasible, in individuals who experience adverse reactions to the drug that are not life-threatening; however, co-trimoxazole should be permanently discontinued and an alternative used in those with life-threatening adverse reactions to the drug.155,156

Alternative regimens recommended by CDC, NIH, IDSA, and AAP for primary and secondary PCP prophylaxis in HIV-infected infants and children who cannot tolerate co-trimoxazole are dapsone (1 month of age or older), atovaquone (1 month of age or older†), or aerosolized pentamidine (5 years of age or older).156

Toxoplasmosis

Atovaquone is used as an alternative for treatment and prevention of toxoplasmosis caused by Toxoplasma gondii †,42,43,134,155,156 and is designated an orphan drug by FDA for primary prophylaxis in HIV-infected individuals at high risk for developing T. gondii encephalitis and for treatment and suppression of T. gondii encephalitis.22

Treatment of Toxoplasmosis

Atovaquone is used in conjunction with pyrimethamine (and leucovorin), in conjunction with sulfadiazine, or alone as an alternative for treatment of toxoplasmosis†, including T. gondii encephalitis in HIV-infected adults and adolescents.134,155 Atovaquone regimens have not been evaluated for treatment of toxoplasmosis in HIV-infected infants and children.156

CDC, NIH, IDSA, and AAP state that pyrimethamine (and leucovorin) in conjunction with sulfadiazine is the regimen of choice for initial treatment of toxoplasmosis, including toxoplasmosis in HIV-infected adults, adolescents, and children.155,156 Pyrimethamine (and leucovorin) in conjunction with clindamycin is the preferred alternative in HIV-infected adults and adolescents who are unable to tolerate sulfadiazine or failed to respond to the regimen of choice.155 CDC, NIH, and IDSA state that other alternative regimens that have been used for treatment of toxoplasmosis in HIV-infected adults and adolescents include co-trimoxazole alone, atovaquone in conjunction with pyrimethamine (and leucovorin), atovaquone in conjunction with sulfadiazine, atovaquone alone, or pyrimethamine (and leucovorin) in conjunction with azithromycin.155 Although these alternative regimens have been effective, comparative efficacies with the preferred and preferred alternative regimens have not been established.155 When a parenteral regimen is required for initial treatment of toxoplasmosis in severely ill HIV-infected adults or adolescents, some experts suggest parenteral co-trimoxazole or a regimen of pyrimethamine (and leucovorin) in conjunction with parenteral clindamycin.155

Pregnant HIV-infected women with suspected or confirmed primary T. gondii infection should be managed in consultation with a specialist in maternal-fetal medicine or other appropriate specialists.155,156 CDC, NIH, and IDSA state that, despite concerns about use of pyrimethamine in pregnant women, treatment of toxoplasmosis in pregnant women generally should be the same as that in nonpregnant adults.155

Pyrimethamine (and leucovorin) in conjunction with sulfadiazine also is the regimen of choice for treatment of congenital toxoplasmosis and for treatment of acquired CNS, ocular, or systemic toxoplasmosis in HIV-infected infants and children.156 The preferred alternative for treatment of toxoplasmosis in neonates and HIV-infected infants and children with sulfonamide sensitivity is pyrimethamine (and leucovorin) in conjunction with clindamycin;156 other alternative regimens that have been used in adults and adolescents have not been adequately studied in children.156 Empiric treatment of congenital toxoplasmosis should be strongly considered in infants born to HIV-infected women who had symptomatic or asymptomatic toxoplasmosis during pregnancy, regardless of whether the mother received toxoplasmosis treatment during the pregnancy.156

Prevention of Toxoplasmosis

Atovaquone is used in conjunction with pyrimethamine (and leucovorin) or alone for primary prophylaxis to prevent initial episodes of toxoplasmosis† in HIV-infected adults, adolescents, and children† and is used in conjunction with pyrimethamine (and leucovorin), in conjunction with sulfadiazine, or alone for chronic maintenance therapy to prevent relapse of toxoplasmosis (secondary prophylaxis)† in HIV-infected individuals.39,134,155

Prevention of Initial Episode (Primary Prophylaxis)

CDC, NIH, and IDSA recommend primary prophylaxis against T. gondii encephalitis in HIV-infected adults and adolescents who are seropositive for Toxoplasma IgG antibody and have CD4⁺ T-cell counts less than 100/mm³.155

CDC, NIH, and IDSA state that primary toxoplasmosis prophylaxis should be discontinued in HIV-infected adults and adolescents who have responded to antiretroviral therapy and have CD4⁺ T-cell counts that have remained greater than 200/mm³ for longer than 3 months.155 Discontinuance of primary toxoplasmosis prophylaxis is recommended in these individuals since it appears to add little benefit in terms of toxoplasmosis disease prevention and discontinuance reduces the medication burden, cost, and potential for toxicity, drug interactions, and selection of drug-resistant pathogens.155 Primary toxoplasmosis prophylaxis should be reinitiated in HIV-infected adults and adolescents if CD4⁺ T-cell counts decrease to less than 100-200/mm³.155

Co-trimoxazole is the drug of choice for primary toxoplasmosis prophylaxis in HIV-infected adults and adolescents.155 Dapsone in conjunction with pyrimethamine (and leucovorin) is the preferred alternative for such prophylaxis in HIV-infected adults and adolescents who cannot tolerate co-trimoxazole.155 CDC, NIH, and IDSA state that other alternatives for primary toxoplasmosis prophylaxis in those who cannot tolerate co-trimoxazole are atovaquone alone or atovaquone in conjunction with pyrimethamine (and leucovorin).155

Prevention of Recurrence (Secondary Prophylaxis)

CDC, NIH, and IDSA state that HIV-infected adults and adolescents who have completed initial treatment of T. gondii encephalitis should receive chronic maintenance therapy (secondary prophylaxis) to prevent relapse.155

CDC, NIH, and IDSA state that secondary toxoplasmosis prophylaxis generally can be discontinued in HIV-infected adults and adolescents who have successfully completed toxoplasmosis treatment, remain asymptomatic with respect to toxoplasmic encephalitis, and have responded to antiretroviral therapy with CD4⁺ T-cell counts that have remained greater than 200/mm³ for longer than 6 months.155 Limited data indicate that such individuals are at low risk for recurrence of toxoplasmic encephalitis.155 However, some experts would obtain a magnetic resonance image of the brain as part of their evaluation to determine whether discontinuance of secondary toxoplasmosis prophylaxis is appropriate.155 Secondary toxoplasmosis prophylaxis should be reinitiated in HIV-infected adults and adolescents if CD4⁺ T-cell counts decrease to less than 200/mm³.155

For secondary toxoplasmosis prophylaxis in HIV-infected adults and adolescents, the regimen of choice is pyrimethamine (and leucovorin) in conjunction with sulfadiazine.155 CDC, NIH, and IDSA state that alternative regimens for secondary toxoplasmosis prophylaxis in HIV-infected adults and adolescents are pyrimethamine (and leucovorin) in conjunction with clindamycin, atovaquone in conjunction with pyrimethamine (and leucovorin), atovaquone in conjunction with sulfadiazine, or atovaquone alone.155 Limited data indicate that co-trimoxazole may be another effective alternative for secondary toxoplasmosis prophylaxis in HIV-infected individuals.155

Primary and Secondary Prophylaxis in Children

Although specific levels of immunosuppression that increase the risk for T. gondii encephalitis in HIV-infected children are less well defined than those for HIV-infected adults and adolescents, CDC, NIH, IDSA, and AAP recommend primary prophylaxis against T. gondii encephalitis in toxoplasma-seropositive HIV-infected children younger than 6 years of age who have CD4⁺ T-cell percentages less than 15% and in toxoplasma-seropositive HIV-infected children 6 years of age or older who have CD4⁺ T-cell counts less than 100/mm³.156 In addition, CDC, NIH, IDSA, and AAP state that all HIV-infected infants and children who have completed initial treatment of T. gondii encephalitis should receive chronic maintenance therapy (secondary prophylaxis) to prevent relapse.156

The safety of discontinuing primary toxoplasmosis prophylaxis in HIV-infected children whose immunologic status improves in response to antiretroviral therapy has not been extensively studied.156 CDC, NIH, IDSA, and AAP state that primary toxoplasmosis prophylaxis should not be discontinued in HIV-infected children younger than 1 year of age.156 However, based on data from adults, these experts state that discontinuance of primary toxoplasmosis prophylaxis can be considered in HIV-infected children 1 to less than 6 years of age who have received at least 6 months of antiretroviral therapy and have CD4⁺ T-cell percentages that have remained at 15% or greater for longer than 3 months.156 In HIV-infected children 6 years of age or older who have received at least 6 months of antiretroviral therapy, primary toxoplasmosis prophylaxis can be discontinued if CD4⁺ T-cell counts have remained greater than 200/mm³ for longer than 3 months.156 Primary toxoplasmosis prophylaxis should be reinitiated if CD4⁺ T-cell percentages decrease to less than 15% in HIV-infected children younger than 6 years of age or if CD4⁺ T-cell counts decrease to less than 100-200/mm³ in HIV-infected children 6 years of age or older.156

The safety of discontinuing secondary toxoplasmosis prophylaxis in HIV-infected children receiving antiretroviral therapy has not been extensively studied.156 However, based on data from adults, CDC, NIH, IDSA, and AAP state that discontinuance of secondary toxoplasmosis prophylaxis can be considered in HIV-infected children 1 to less than 6 years of age who have successfully completed toxoplasmosis treatment, remain asymptomatic with respect to toxoplasmic encephalitis, have received more than 6 months of stable antiretroviral therapy, and have CD4⁺ T-cell percentages that have remained at 15% or greater for more than 6 consecutive months.156 In HIV-infected children 6 years of age or older who have successfully completed toxoplasmosis treatment, remain asymptomatic with respect to toxoplasmic encephalitis, and have received more than 6 months of antiretroviral therapy, consideration can be given to discontinuing secondary toxoplasmosis prophylaxis if CD4⁺ T-cell counts have remained greater than 200/mm³ for more than 6 consecutive months.156 Secondary toxoplasmosis prophylaxis should be reinitiated in HIV-infected children if these age-based parameters are not met.156

For primary toxoplasmosis prophylaxis in HIV-infected infants and children, the drug of choice is co-trimoxazole.156 Dapsone in conjunction with pyrimethamine (and leucovorin) is the preferred alternative for such prophylaxis in those 1 month of age or older who cannot tolerate co-trimoxazole.156 CDC, NIH, IDSA, and AAP state that atovaquone alone is another alternative for primary toxoplasmosis prophylaxis in HIV-infected children and adolescents 1 month of age or older; those 4-24 months of age can receive atovaquone alone or in conjunction with pyrimethamine (and leucovorin).156

For secondary prophylaxis to prevent recurrence of toxoplasmosis in HIV-infected infants and children, the regimen of choice is sulfadiazine in conjunction with pyrimethamine (and leucovorin);156 pyrimethamine (and leucovorin) in conjunction with clindamycin is the preferred alternative for such prophylaxis in those who cannot tolerate sulfadiazine.156 CDC, NIH, IDSA, and AAP state that atovaquone alone is another alternative for secondary toxoplasmosis prophylaxis in HIV-infected children and adolescents 1 month of age or older; those 4-24 months of age can receive atovaquone alone or in conjunction with pyrimethamine (and leucovorin).156 Limited data indicate that co-trimoxazole may be another effective alternative for secondary toxoplasmosis prophylaxis in HIV-infected individuals,155,156 but is recommended in children only when pyrimethamine regimens are not tolerated.156

Babesiosis

Atovaquone is used in conjunction with azithromycin for treatment of babesiosis† caused by Babesia microti .105,134,178,181

Although several species of Babesia can infect humans, B. microti is the most common cause of babesiosis in the US.178 B. microti is transmitted by Ixodes scapularis ticks, which also may be simultaneously infected with and transmit Borrelia burgdorferi (causative agent of Lyme disease) and Anaplasma phagocytophilum (causative agent of human granulocytotropic anaplasmosis [HGA, formerly known as human granulocytic ehrlichiosis]).105,178 Therefore, the possibility of coinfection with B. burgdorferi and/or A. phagocytophilum should be considered in patients who have severe or persistent symptoms despite appropriate anti-infective treatment for babesiosis.178 (See Lyme Disease in Uses: Spirochetal Infections and see Uses: Ehrlichiosis and Anaplasmosis, in the Tetracyclines General Statement 8:12.24.)

IDSA states that all patients with active babesiosis (i.e., symptoms of viral-like infection and identification of babesial parasites in blood smears or by polymerase chain reaction [PCR] amplification of babesial DNA) should receive anti-infective treatment because of the risk of complications; however, symptomatic patients whose serum contains antibody to babesia but whose blood lacks identifiable babesial parasites on smear or babesial DNA by PCR should not receive treatment.178 In addition, treatment is not recommended initially for asymptomatic individuals, regardless of the results of serologic examination, blood smears, or PCR, but should be considered if parasitemia persists for longer than 3 months.178

When anti-infective treatment of babesiosis is indicated, IDSA and other clinicians recommend either a regimen of clindamycin and quinine or a regimen of atovaquone and azithromycin.105,134,178,181 The clindamycin and quinine regimen may be preferred in those with severe babesiosis.178 However, there is some evidence that, in patients with mild or moderate illness, the atovaquone and azithromycin regimen may be as effective and better tolerated than the clindamycin and quinine regimen.105,134,178,181 Patients with moderate to severe babesiosis should be monitored closely during treatment to ensure clinical improvement.178 Exchange transfusions have been used successfully in asplenic patients with life-threatening babesiosis, especially in severely ill patients with high levels of parasitemia (10% or more), significant hemolysis, or compromised renal, hepatic, or pulmonary function.105,134,178

Malaria

Results of studies evaluating use of atovaquone alone for treatment of Plasmodium falciparum malaria† indicate that, although an initial clinical response may occur, use of the drug alone is associated with an unacceptable rate of recrudescent parasitemia.44,45 Therefore, atovaquone should not be used alone for treatment of malaria.44,45

A fixed-combination preparation containing atovaquone and proguanil hydrochloride (atovaquone/proguanil) is commercially available for treatment and prevention of malaria caused by P. falciparum , including chloroquine-resistant P. falciparum malaria.41,44,134 (See Atovaquone and Proguanil Hydrochloride 8:30.08.)

Administration

Atovaquone is administered orally.1

Atovaquone must be taken with food to optimize GI absorption.1 (See Pharmacokinetics: Absorption.) Alternative therapy should be considered in patients who have difficulty taking atovaquone with food.1

The multiple-dose bottle containing atovaquone oral suspension should be shaken gently before removing a dose.1

If a single-dose foil pouch containing atovaquone oral suspension is used, the pouch should be opened by removing the perforated tab and the entire contents of the pouch ingested; the dose can be discharged from the pouch into a dosing spoon or cup or directly into the mouth.1

Dosage

Pneumocystis jirovecii Pneumonia

Treatment of Pneumocystis jirovecii Pneumonia

When atovaquone monotherapy is used as an alternative for treatment of mild to moderate Pneumocystis jirovecii (formerly Pneumocystis carinii ) pneumonia (PCP) in adults and adolescents 13 years of age or older, including those with human immunodeficiency virus (HIV) infection, the usual dosage is 750 mg twice daily given for 21 days.1,134,155,156

When atovaquone monotherapy is used as an alternative for treatment of mild to moderate PCP in HIV-infected children and infants 1 month of age or older†, the US Centers for Disease Control and Prevention (CDC), National Institutes of Health (NIH), Infectious Diseases Society of America (IDSA), American Academy of Pediatrics (AAP), and others recommend a dosage of 30-40 mg/kg once daily in those 1-3 months of age, 45 mg/kg once daily in those 4-24 months of age, and 30-40 mg/kg once daily in those older than 24 months to 12 years of age given for 21 days.134,156 Alternatively, some experts recommend that infants 1-3 months of age receive 15-20 mg/kg twice daily, infants 4-24 months of age receive 22.5 mg/kg twice daily, and children older than 24 months to 12 years of age receive 15-20 mg/kg twice daily given for 21 days.156

Prevention of Initial Episode (Primary Prophylaxis)

When atovaquone is used as an alternative for primary prophylaxis of PCP in adults and adolescents 13 years of age or older, including HIV-infected individuals, the usual dosage is 1.5 g once daily1,134,155,156 given alone or, alternatively, in conjunction with oral pyrimethamine (25 mg once daily) and oral leucovorin (10 mg once daily).155 CDC, NIH, and IDSA state that primary PCP prophylaxis should be discontinued in HIV-infected adults and adolescents if CD4⁺ T-cell counts have remained greater than 200/mm³ for longer than 3 months in response to antiretroviral therapy, but should be reinitiated if CD4⁺ T-cell counts decrease to less than 200/mm³.155 (See Prevention of Pneumocystis jirovecii Infections under Uses: Pneumocystis jirovecii Pneumonia.)

When atovaquone monotherapy is used as an alternative for primary PCP prophylaxis in HIV-infected children and infants 1 month of age or older†, CDC, NIH, IDSA, AAP, and others recommend a dosage of 30-40 mg/kg once daily in those 1-3 months of age, 45 mg/kg once daily in those 4-24 months of age, and 30-40 mg/kg once daily in those older than 24 months to 12 years of age.134,156 In HIV-infected children 1 year of age or older who have received at least 6 months of antiretroviral therapy, CDC, NIH, IDSA, and AAP state that discontinuance of primary PCP prophylaxis should be considered based on age-related CD4⁺ T-cell counts or CD4⁺ T-cell percentages, but should be reinitiated if these parameters decrease below the age-related thresholds.156 (See Primary and Secondary Prophylaxis in Children under Pneumocystis jirovecii Pneumonia: Prevention of Pneumocystis jirovecii Infections, in Uses.)

Prevention of Recurrence (Secondary Prophylaxis)

When atovaquone is used as an alternative for secondary PCP prophylaxis in adults and adolescents 13 years of age or older, including those with HIV infection, the usual dosage is 1.5 g once daily1,134,155,156 given alone or, alternatively, in conjunction with oral pyrimethamine (25 mg once daily) and oral leucovorin (10 mg once daily).155 CDC, NIH, and IDSA state that secondary PCP prophylaxis generally can be discontinued in HIV-infected adults and adolescents if CD4⁺ T-cell counts have remained greater than 200/mm³ for longer than 3 months in response to antiretroviral therapy, but should be reinitiated if CD4⁺ T-cell counts decrease to less than 200/mm³.155 However, secondary PCP prophylaxis probably should be continued for life (regardless of CD4⁺ T-cell count) if PCP occurred or recurred when CD4⁺ T-cell counts were greater than 200/mm³.155 (See Prevention of Pneumocystis jirovecii Infections under Uses: Pneumocystis jirovecii Pneumonia.)

When atovaquone monotherapy is used as an alternative for secondary PCP prophylaxis in HIV-infected children and infants 1 month of age or older†, CDC, NIH, IDSA, AAP, and others recommend a dosage of 30-40 mg/kg once daily in those 1-3 months of age, 45 mg/kg once daily in those 4-24 months of age, and 30-40 mg/kg once daily in those older than 24 months to 12 years of age.134,156 In HIV-infected children 1 year of age or older who have received at least 6 months of antiretroviral therapy, CDC, NIH, IDSA, and AAP state that discontinuance of secondary PCP prophylaxis should be considered based on age-related CD4⁺ T-cell counts or CD4⁺ T-cell percentages, but should be reinitiated if these parameters decrease below the age-related thresholds.156 (See Primary and Secondary Prophylaxis in Children under Pneumocystis jirovecii Pneumonia: Prevention of Pneumocystis jirovecii Infections, in Uses.)

Toxoplasmosis

Treatment of Toxoplasmosis

When used as an alternative for treatment of toxoplasmosis† in HIV-infected adults and adolescents, atovaquone is given in a dosage of 1.5 g twice daily in conjunction with oral pyrimethamine (200-mg loading dose, then 50 mg once daily in those weighing less than 60 kg or 75 mg once daily in those weighing 60 kg or more) and oral leucovorin (10-25 mg once daily; may be increased to 50 mg once or twice daily).155

Alternatively, HIV-infected adults and adolescents can receive atovaquone in a dosage of 1.5 g twice daily in conjunction with oral sulfadiazine (1 g every 6 hours in those weighing less than 60 kg or 1.5 g every 6 hours in those weighing 60 kg or more) for treatment of toxoplasmosis†.155

Alternatively, HIV-infected adults and adolescents can receive atovaquone in a dosage of 1.5 g twice daily alone for treatment of toxoplasmosis†.155

The treatment regimen should be continued for at least 6 weeks; a longer duration may be appropriate if clinical or radiologic disease is extensive or there is an incomplete response at 6 weeks.155

Prevention of Initial Episode (Primary Prophylaxis)

When used as an alternative for primary prophylaxis of toxoplasmosis† in HIV-infected adults and adolescents, CDC, NIH, and IDSA recommend that atovaquone be given in a dosage of 1.5 g once daily either alone or, alternatively, in conjunction with oral pyrimethamine (25 mg once daily) and oral leucovorin (10 mg once daily).155

When used as an alternative for primary prophylaxis of toxoplasmosis in HIV-infected children and infants 1 month of age or older†, CDC, NIH, IDSA, and AAP recommend that atovaquone be given alone in a dosage of 30 mg/kg once daily in those 1-3 months of age or older than 24 months of age.156 In those 4-24 months of age, these experts recommend that atovaquone be given in a dosage of 45 mg/kg once daily alone or, alternatively, in conjunction with oral pyrimethamine (1 mg/kg or 15 mg/m² [up to 25 mg] once daily) and oral leucovorin (5 mg every 3 days).156

CDC, NIH, and IDSA state that primary toxoplasmosis prophylaxis should be discontinued in HIV-infected adults and adolescents who have CD4⁺ T-cell counts that have remained greater than 200/mm³ for longer than 3 months in response to antiretroviral therapy,155 but should be reinitiated if CD4⁺ T-cell counts decrease to less than 100-200/mm³.155 The safety of discontinuing primary toxoplasmosis prophylaxis in HIV-infected children whose immunologic status improves on antiretroviral therapy has not been extensively studied.156 (See Prevention of Toxoplasmosis under Uses: Toxoplasmosis.)

Prevention of Recurrence (Secondary Prophylaxis)

When used as an alternative for long-term suppressive or chronic maintenance therapy (secondary prophylaxis) to prevent recurrence of toxoplasmic encephalitis in HIV-infected adults and adolescents†, CDC, NIH, and IDSA recommend that atovaquone be given in a dosage of 750-1500 mg twice daily in conjunction with oral pyrimethamine (25 mg once daily) and oral leucovorin (10 mg once daily) or, alternatively, in conjunction with oral sulfadiazine (2-4 g daily in 2-4 divided doses).155 Alternatively, HIV-infected adults and adolescents can receive atovaquone in a dosage of 750-1500 mg twice daily alone.155

When used as an alternative for secondary toxoplasmosis prophylaxis in HIV-infected children and infants 1 month of age or older†, CDC, NIH, IDSA, and AAP recommend that atovaquone be given alone in a dosage of 30 mg/kg once daily in those 1-3 months of age or older than 24 months of age.156 In those 4-24 months of age, these experts recommend that atovaquone be given in a dosage of 45 mg/kg once daily alone or, alternatively, in conjunction with oral pyrimethamine (1 mg/kg or 15 mg/m² [up to 25 mg] once daily) and oral leucovorin (5 mg every 3 days).156

CDC, NIH, and IDSA state that secondary toxoplasmosis prophylaxis generally can be discontinued in HIV-infected adults and adolescents who have successfully completed toxoplasmosis treatment, remain asymptomatic with respect to toxoplasmic encephalitis, and have CD4⁺ T-cell counts that have remained greater than 200/mm³ for longer than 6 months in response to antiretroviral therapy.155 The safety of discontinuing secondary toxoplasmosis prophylaxis in HIV-infected children receiving antiretroviral therapy has not been extensively studied.156 (See Prevention of Toxoplasmosis under Uses: Toxoplasmosis.)

Babesiosis

For treatment of babesiosis† caused by Babesia microti , IDSA recommends that adults receive atovaquone in a dosage of 750 mg twice daily for 7-10 days in conjunction with oral azithromycin (0.5-1 g on day 1, then 250 mg once daily for a total of 7-10 days; immunocompromised patients should receive an azithromycin dosage of 0.6-1 g daily).178

For treatment of babesiosis† in pediatric patients. IDSA and other clinicians recommend that atovaquone be given in a dosage of 20 mg/kg (up to 750 mg) twice daily for 7-10 days in conjunction with oral azithromycin (10 mg/kg [up to 500 mg] once on day 1, then 5 mg/kg [up to 250 mg] once daily for a total of 7-10 days).134,178

Dosage in Renal and Hepatic Impairment

The pharmacokinetics of atovaquone in individuals with renal or hepatic impairment and the possible need for caution and/or dosage adjustment remain to be fully determined.1 The manufacturer states that atovaquone should be used with caution and close monitoring in patients with severe hepatic impairment.1

Although adverse effects associated with atovaquone therapy are common, the drug generally appears to be well tolerated.1,3,24,26 The most frequent adverse effects of atovaquone include rash, GI effects, fever, and headache.1,3,24,26,28

In controlled clinical trials that evaluated atovaquone for treatment or prevention of Pneumocystis jirovecii (formerly Pneumocystis carinii ) pneumonia (PCP), adverse effects were severe enough to require discontinuance of the drug in 9 or 25% of patients, respectively;1 there were no reports of adverse effects that were life-threatening or fatal.1,30 Because most HIV-infected patients receiving atovaquone have serious underlying disease with multiple baseline symptomatology and clinical abnormalities, many reported effects may not be directly attributable to the drug.1 In controlled clinical trials evaluating atovaquone for treatment of PCP,1,24,26 adverse effects were reported in 63% of patients receiving atovaquone and in 65 or 72% of those receiving oral co-trimoxazole or IV pentamidine, respectively.1 Treatment-limiting adverse effects were substantially less common with atovaquone than with co-trimoxazole or pentamidine.1,24,26 In one comparative study evaluating atovaquone for prevention of PCP, adverse effects were reported in 98 or 89% of individuals receiving atovaquone or aerosolized pentamidine, respectively.1 In another clinical study, adverse effects were reported in 20.2 or 43.4% of individuals receiving atovaquone or dapsone, respectively.1

Dermatologic and Sensitivity Reactions

Rash,1,3,5,7,15,24,26,27 which may be maculopapular,1,5 erythematous,15 or bullous,27 is the most common adverse effect of atovaquone, occurring in up to 39% of patients receiving the drug in controlled clinical trials.1,24 Rash generally is mild to moderate in severity,1,3 usually does not require discontinuance of the drug,1 and may resolve despite continued treatment.3,26 However, rash occasionally may be severe enough to require discontinuance of atovaquone.1,3,26,27 In controlled clinical trials, rash required discontinuance of the drug in 4-6% of patients.1,24,26 There is some evidence that rash may be associated with increased steady-state plasma concentrations of atovaquone.3,26,32

Hypersensitivity reactions have been reported in up to 1% of patients receiving atovaquone in clinical studies.1 Pruritus1,24 was reported in 5% of patients receiving the drug in controlled clinical trials.1 There have been postmarketing reports of bronchospasm, throat tightness, and urticaria.1

Erythema multiforme has occurred rarely in patients receiving atovaquone.1,3,27 Stevens-Johnson syndrome and skin desquamation have been reported in patients receiving a multiple-drug regimen that included atovaquone.1

GI Effects

Adverse GI effects are among the most frequently reported effects of atovaquone.1,7,15,24,26 Nausea1,7,15,24,26 occurred in up to 26%,1 diarrhea1,15,24 in up to 42%,1,24 and vomiting1,24,26 in up to 15% of patients1,24 receiving the drug in controlled clinical trials. Vomiting was the only adverse effect besides rash that required discontinuance of atovaquone in more than one patient in controlled clinical trials evaluating the drug for treatment of PCP.1,28 Approximately 4 or 3% of patients receiving atovaquone for PCP prophylaxis discontinued the drug because of diarrhea or nausea, respectively.1 Increased serum amylase concentration1,26 (exceeding 1.5 times the upper limit of normal)1 was reported in 8% of patients receiving the drug in controlled clinical trials.1 Abdominal pain1,28 was reported in up to 20%,1 constipation1,24 in 3%,1,24 anorexia1,28 in 7%,1 and dyspepsia1,28 in 5% of patients1 receiving atovaquone in controlled clinical trials. Taste perversion1,26,28 was reported in 3% of patients.1 Increased appetite has occurred rarely.5 Absorption of atovaquone may be limited in patients with a GI disorder.1 (See Cautions: Precautions and Contraindications.)

Nervous System Effects

Headache1,28 is the most frequent adverse nervous system effect of atovaquone,1 occurring in up to 28% of patients receiving the drug in controlled clinical trials.1 Insomnia1,28 occurred in up to 10%,1 asthenia1,28 in up to 22%,1 dizziness1,24 in up to 8%,1 and anxiety1,28 in up to 7% of patients1 receiving atovaquone in controlled clinical trials. Pain1,28 was reported in up to 10% of patients receiving the drug,1 and dementia has been reported rarely.26

Hematologic Effects

The most common adverse hematologic effect of atovaquone is anemia (hemoglobin less than 8 g/dL, a decrease in hemoglobin of at least 2 g/dL, or need for transfusion),1,3 which occurred in about 6% of patients receiving the drug in controlled clinical trials.1 Neutropenia1,3 (absolute neutrophil count less than 750/mm³)1 was reported in 3% of patients receiving atovaquone in controlled clinical trials.1 Methemoglobinemia1 or thrombocytopenia1 has been reported in patients receiving atovaquone.1

Hepatic Effects

Increased serum alkaline phosphatase concentrations (exceeding 2.5 times the upper limit of normal) were reported in about 8% of patients receiving atovaquone in controlled clinical trials.1 Increases (exceeding 5 times the upper limit of normal) in serum concentrations of ALT1,3,5 and AST1,3,5,7 were reported in 6 and 4% of patients, respectively, receiving the drug in controlled clinical trials.1 In controlled clinical trials, about 2% of patients discontinued atovaquone because of increased serum ALT or AST concentrations.1 Increases in serum bilirubin concentrations have occurred rarely in patients receiving the drug.5

There have been rare reports of hepatitis and at least one case of fatal liver failure in patients receiving atovaquone.1 A causal relationship between atovaquone and these events was not established because of confounding medical conditions and concomitant drug therapies.1

Pancreatitis has been reported in atovaquone-treated patients.1

Renal and Electrolyte Effects

Increased BUN1,26 and serum creatinine concentrations1,26 have been reported rarely in patients receiving atovaquone and occasionally have required discontinuance of the drug.1,26

Hyponatremia (less than 0.96 times the lower limit of normal range) was reported in up to 10% of patients receiving atovaquone in controlled clinical trials.1 Acute renal impairment has occurred in patients receiving atovaquone.1

Metabolic Effects

Hyperglycemia (exceeding 1.8 times the upper limit of normal) occurred in 9% of patients receiving atovaquone in controlled clinical trials.1 Hypoglycemia1,26,28 has occurred rarely.1

Other Adverse Effects

Fever1,3,15,24,26,28 was reported in up to 40% of patients receiving atovaquone in controlled clinical trials1 and occasionally has required discontinuance of the drug.3,4,24,26,28 Oral candidiasis1,28 was reported in 10%,1 cough1,26,28 in 25%,1 sweating1,28 in 10%,1 sinusitis1,28 in 7%, and rhinitis1,28 in 24% of patients1 receiving atovaquone in controlled clinical trials. Infection1 or dyspnea1 has occurred in 22 or 15% of patients receiving atovaquone.1 Hypotension,1,26,28 vortex keratopathy,1 transient sinus arrhythmia,5 increased serum creatine kinase (CK, creatine phosphokinase, CPK) concentrations,5 and transient conjunctivitis27 also have been reported rarely.

Precautions and Contraindications

Atovaquone is contraindicated in patients who develop or have had a history of potentially life-threatening hypersensitivity reactions to the drug or any component of the formulation.1

Clinical experience with use of atovaquone for treatment of PCP has been limited to patients with mild to moderate infections (alveolar-arterial oxygen diffusion gradient [P_A-aD] of 45 mm Hg or less).1 The drug has not been evaluated systematically for use in patients with more severe PCP or for use in patients who fail to respond to co-trimoxazole treatment.1 Clinical deterioration during atovaquone treatment of PCP could represent secondary infection with a nonsusceptible pathogen and/or progression of PCP.1 Atovaquone is not effective therapy for concurrent pulmonary conditions such as bacterial, viral, or fungal pneumonia or mycobacterial diseases.1 All patients with acute PCP for whom atovaquone treatment is being considered should be evaluated carefully for other possible causes of pulmonary disease and treated with additional agents as appropriate.1

Patients should be instructed carefully regarding the importance of taking atovaquone concomitantly with food and the need to follow the prescribed dosage.1

If achievement of adequate plasma atovaquone concentrations does not appear likely in any patient for whom therapy with the drug is being considered (e.g., those who have difficulty taking the drug with food), alternatives should be used.1 Atovaquone should be used with caution in patients with a GI disorder (e.g., chronic diarrhea, malabsorption syndrome), since absorption of the drug may be limited in these patients, possibly resulting in lower plasma concentrations than are required for adequate therapeutic response.1

If atovaquone is given to patients with severe hepatic impairment, caution and close monitoring are advised.1

Pediatric Precautions

The manufacturer states that safety and efficacy of atovaquone in children have not been established.1 A relationship between atovaquone plasma concentrations and successful treatment of PCP has been established in adults.1 One study evaluating the pharmacokinetics and safety of atovaquone in children 4 months of age or older suggested that the drug is well tolerated in this age group.15,30 Results of a study using atovaquone oral suspension in HIV-infected, asymptomatic children 1 month to 13 years of age suggest that the pharmacokinetics of the drug is age related.1 The drug was well tolerated in these children.1

Geriatric Precautions

Although studies used to establish efficacy of atovaquone did not include a sufficient number of individuals 65 years of age or older to determine whether geriatric individuals respond differently to the drug than younger individuals, clinical experience to date has not identified differences in response between geriatric and younger adults.1

The manufacturer recommends that atovaquone dosage for geriatric patients be selected with caution because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.1

Mutagenicity and Carcinogenicity

Atovaquone was not mutagenic in the Ames microbial ( Salmonella ) mutagen test, with or without metabolic activation,1,15 or in assays using mouse lymphoma1 or cultured human lymphocyte cells.1,15 The drug was not genotoxic in vivo in the mouse micronucleus assay.1

No evidence of carcinogenicity was observed in studies in rats.1 In 24-month studies in mice, a treatment-related increased incidence in hepatocellular adenoma and hepatocellular carcinoma was observed at all doses evaluated (animal exposure ranged from 1.4-3.6 times the average steady-state atovaquone plasma concentration in humans receiving the drug for treatment of PCP).1

Pregnancy, Fertility, and Lactation

Pregnancy

Reproduction studies in rats using atovaquone dosages resulting in plasma concentrations up to 2-3 times the estimated human exposure have not revealed evidence of teratogenicity.1,15 However, maternal and fetal toxicity (decreased mean fetal body lengths and weights and increased early fetal resorption and postimplantation fetal loss) did occur in rabbits receiving oral atovaquone dosages resulting in plasma concentrations approximately one-half the estimated human exposure.1,15 It is not clear whether these effects were caused by atovaquone or resulted from maternal toxicity.1 Atovaquone concentrations in rabbit fetuses averaged 30% of concurrent maternal plasma concentrations.1 In another study, atovaquone concentrations in rat fetuses following single ¹⁴C-radiolabeled doses were 18% (middle gestation) and 60% (late gestation) of concurrent maternal plasma concentrations.1 There are no adequate and controlled studies to date using atovaquone in pregnant women, and the drug should be used during pregnancy only when the potential benefits justify the possible risks to the fetus.1

Fertility

Reproduction studies in rats using atovaquone dosages up to 1 g/kg daily15 (resulting in plasma concentrations up to 5 times the estimated human exposure)1 have not revealed evidence of impaired fertility.1

Lactation

It is not known whether atovaquone is distributed into human milk.1 The drug is distributed into breast milk of rats in concentrations 30% of concurrent maternal plasma concentrations.1 Atovaquone should be used with caution in nursing women.1

Protein-bound Drugs

Because atovaquone is highly bound to plasma proteins (99.9%), the drug should be used with caution in patients receiving other highly plasma protein-bound drugs with narrow therapeutic indices since competition for binding sites may occur.1

Antimycobacterial Agents

In HIV-infected adults, concomitant use of rifampin (600 mg once daily) and atovaquone suspension (750 mg twice daily) resulted in a 52% decrease in average steady-state plasma atovaquone concentrations and about a 40% decrease in the average plasma half-life of the drug; in addition, there was a 37% increase in the average steady-state plasma rifampin concentrations.1 It has been suggested that alternatives to rifampin be considered in patients receiving atovaquone.1

Although specific studies have not been performed, it is possible that similar drug interactions could occur if rifabutin is used concomitantly with atovaquone since the drug is structurally similar to rifampin.1

Co-trimoxazole

Concomitant use of atovaquone suspension (500 mg once daily) and co-trimoxazole (800 mg of sulfamethoxazole and 160 mg of trimethoprim twice daily) had no clinically important effect on steady-state plasma concentrations of atovaquone.1 Although steady-state plasma concentrations of sulfamethoxazole and trimethoprim were decreased slightly, the effect is not expected to be clinically important.1

Metoclopramide

Concomitant use of metoclopramide and the fixed combination of atovaquone and proguanil hydrochloride (atovaquone/proguanil) has resulted in decreased bioavailability of atovaquone.41 Metoclopramide and atovaquone should be used concomitantly only if other antiemetics are not available.41

Phenytoin

Plasma protein binding of atovaquone does not appear to be affected by therapeutic concentrations of phenytoin (i.e., 15 mcg/mL) and vice versa.1

Tetracycline

Concomitant use of tetracycline and the fixed combination of atovaquone and proguanil hydrochloride (atovaquone/proguanil) has resulted in a 40% decrease in atovaquone plasma concentrations.41

Zidovudine

Although concomitant atovaquone can increase oral bioavailability of zidovudine,31 the clinical importance of this finding is not known.15 In a study in HIV-infected individuals who received atovaquone (750 mg orally twice daily) and zidovudine (200 mg orally every 8 hours), the apparent oral clearance of zidovudine and the ratio of glucuronide metabolite to parent compound was decreased; however, the effect was minor and would not be expected to produce clinically important effects.1 Zidovudine has no effect on the pharmacokinetics of atovaquone.1

Mechanism of Action

The exact mechanism(s) of antiprotozoal action of hydroxynaphthoquinone derivatives, including atovaquone, has not been fully elucidated.5,11,12,15 The antiprotozoal activity of the drugs may be related principally to their ability to inhibit selectively mitochondrial electron transport with consequent inhibition of de novo pyrimidine synthesis.3,5,7,8,10,11,12,13,15,17,24 Unlike mammalian cells, certain protozoa are unable to salvage preformed pyrimidines, thus accounting for the preferential susceptibility (e.g., relative to human cells) of the latter organisms to the toxic effects of the drug.3,7,10,15,17 Hydroxynaphthoquinones may act as analogs of ubiquinone, which is involved in mitochondrial electron transport via dihydroorotate dehydrogenase, an important enzyme in pyrimidine synthesis.3,5,11,13,15 The site of action in the mitochondrial electron transport chain appears to be the cytochrome bc ₁ complex (complex III).3,5,15

The mechanism of action of atovaquone against Pneumocystis jirovecii (formerly Pneumocystis carinii ) has not been fully elucidated.1

Spectrum

Atovaquone is active in vitro and/or in vivo against a variety of protozoa,3,5,11,12,14,15,16,17 including Toxoplasma gondii 11,15 and Plasmodium .14,15,41 Atovaquone also is active against the fungus Pneumocystis jirovecii (formerly Pneumocystis carinii ).1,3,5,7,12,15,16,17

Resistance

Pneumocystis jirovecii (formerly Pneumocystis carinii ) with phenotypic resistance to atovaquone has not been identified in vitro.1 Although the clinical importance is unknown, clinical isolates of P. jirovecii with amino acid substitutions in cytochrome b (a likely target for atovaquone) have been obtained from several patients who developed P. carinii pneumonia (PCP) after receiving atovaquone prophylaxis.1

Pharmacokinetics

Absorption

Bioavailability of orally administered atovaquone is highly dependent on formulation and diet.1

The commercially available oral suspension of atovaquone is approximately twofold more bioavailable in the fasting or fed state compared with the previously available tablet formulation of the drug.1 In HIV-infected adults, the absolute bioavailability of a 750-mg dose of atovaquone given under fed conditions was approximately 47% when the dose was given as the oral suspension compared with approximately 23% when the dose was given as tablets (no longer commercially available in the US).1

Absorption of atovaquone is increased approximately twofold when administered with food.1 In HIV-infected adults receiving 500 mg of atovaquone daily as the oral suspension, peak plasma concentrations were approximately 15.1 mcg/mL when the drug was administered with food (400 kcal, 23 g fat) compared with approximately 8.8. mcg/mL when administered in the fasting state.1

Plasma concentrations of atovaquone do not increase proportionally with the dose.1 In adults, when atovaquone oral suspension was administered with food in a dosage of 500 mg, 750 mg, or 1 g once daily, peak plasma concentrations of the drug were 15.1, 15.3, or 16.8 mcg/mL, respectively, and average steady-state plasma concentrations were 11.7, 12.5, or 13.5 mcg/mL, respectively.1

In a study in HIV-infected, asymptomatic infants and children 1 month to 13 years of age, the pharmacokinetics of atovaquone were age related.1 When the oral suspension was given once daily with food in a dosage of 30 mg/kg for 12 days, average steady-state plasma concentrations of atovaquone were 27.8, 9.8, or 37.1 mcg/mL in those 1-3 months, older than 3 months to 24 months, or older than 2 years to 13 years of age, respectively,1

Distribution

Following IV administration, the volume of distribution of atovaquone at steady state is 0.6 L/kg.1

Atovaquone is extensively (99.9%) bound to plasma proteins.1

Low concentrations of atovaquone (less than 1% of plasma concentrations) were attained in CSF in 3 HIV-infected children receiving atovaquone tablets (no longer commercially available in the US) in a dosage of 750 mg 4 times daily for 2 weeks.1

Animal studies indicate that atovaquone crosses the placenta.1

Atovaquone is distributed into milk in rats in concentrations approximately 30% of concurrent maternal plasma concentrations.1 It is not known whether atovaquone is distributed into human milk.1

Elimination

There is some evidence that atovaquone undergoes limited metabolism; however, a specific metabolite has not been identified.1

The half-life of atovaquone following administration of the oral suspension has ranged from 67-78 hours.1

Atovaquone is presumed to undergo enterohepatic recirculation and is eventually eliminated in feces.1 More than 94% of an atovaquone dose is excreted unchanged in feces over 21 days;1 less than 0.6% is eliminated in urine.1

Studies using the fixed combination of atovaquone and proguanil hydrochloride (atovaquone/proguanil) indicate that there are no marked differences in the rate or extent of systemic exposure to atovaquone in patients with mild or moderate hepatic impairment, but the elimination half-life of atovaquone is prolonged in those with moderate hepatic impairment.41

Studies using atovaquone/proguanil indicate that clearance of atovaquone in patients with mild or moderate renal impairment is similar to that in those with normal renal function,41 but peak plasma concentrations and area under the plasma concentration-time curve (AUC) of atovaquone are decreased in those with severe renal impairment (creatinine clearance less than 30 mL/minute).41

Chemistry and Stability

Chemistry

Atovaquone is a synthetic hydroxynaphthoquinone-derivative antiprotozoal agent.1,7,8,10,15,17 Atovaquone is structurally and pharmacologically related to other hydroxynaphthoquinone derivatives (e.g., lapinone, menoctone, parvaquone, BW 58C), which initially were investigated for antimalarial activity.5,8,10,11,12,13,14,15 Various hydroxynaphthoquinones also have been shown to exhibit antiprotozoal activity (e.g., against toxoplasma, trypanosomes).3,5,8,11,14,15,16

Atovaquone is commercially available for oral administration as an oral suspension.1 Atovaquone also is commercially available for oral administration in fixed combination with proguanil hydrochloride (atovaquone/proguanil).41 (See Atovaquone and Proguanil Hydrochloride 8:30.08.)

Stability

Atovaquone oral suspension should be stored at 15-25°C and should not be frozen.1

1. GlaxoSmithKline. Mepron^® (atovaquone) oral suspension prescribing information. Research Triangle Park, NC; 2013 Mar.

2. Nightingale SL. From the Food and Drug Administration. JAMA . 1992; 267:339. [PubMed 1727943]

3. Falloon J, Kovacs J, Hughes W et al. A preliminary evaluation of 566C80 for the treatment of pneumocystis pneumonia in patients with the acquired immunodeficiency syndrome. New Engl J Med . 1991; 325:1534-8. [PubMed 1944437]

4. Hughes WT. A new drug (566C80) for the treatment of pneumocystis carinii pneumonia. Ann Intern Med . 1992; 116:953-4. [PubMed 1580456]

5. Hughes WT, Kennedy W, Shenep JL et al. Safety and pharmacokinetics of 566C80, a hydroxynaphthoquinone with anti-pneumocystis carinii activity: a phase I study in human immunodeficiency virus (HIV)-infected men. J Infect Dis . 1991; 163:843-8. [PubMed 2010637]

6. Anon. FDA authorizes wider use of new oral medication for AIDS. Oncology . 1991; 5:59.

7. Dohn MN, Frame PT, Baughman RP et al. Open-label efficacy and safety trial of 42 days of 566C80 for Pneumocystis carinii pneumonia in AIDS patients. J Protozool . 1991; 38:220-1S.

8. Hudson AT, Randall AW, Fry M et al. Novel anti-malarial hydroxynaphthoquinones with potent broad spectrum anti-protozoal activity. Parasitology . 1985; 90:45-55. [PubMed 3920634]

9. Wong RJ. Highlights of the Seventh International Conference on AIDS. Clin Pharm . 1991; 10:809-22. [PubMed 1686580]

10. Gutteridge WE. Antimalarial drugs currently in development. J R Soc Med . 1989; 17:63-6.

11. Araujo FG, Huskinson J, Remington JS. Remarkable in vitro and in vivo activities of the hydroxynaphthoquinone 566C80 against tachyzoites and tissue cysts of Toxoplasma gondii . Antimicrob Agents Chemother . 1991; 35: 293-9.

12. Hughes WT, Gray VL, Gutteridge WE et al. Efficacy of a hydroxynaphthoquinone, 566C80, in experimental Pneumocystis carinii pneumonitis. Antimicrob Agents Chemother . 1990; 34:225-8. [PubMed 2327770][PubMedCentral]

13. Hammond DJ, Burchell JR, Pudney M. Inhibition of pyrimidine biosynthesis de novo in Plasmodium falciparum by 2-(4-t-butylcyclohexyl)-3-hydroxy-1, 4-naphthoquinone in vitro. Mol Biochem Parasitol . 1985; 14:97-109. [PubMed 3885032]

14. Davies CS, Pudney M, Matthews PJ et al. The causal prophylactic activity of the novel hydroxynaphthoquinone 566C80 against Plasmodium berghei infections in rats. Acta Leiden . 1989; 58:115-28. [PubMed 2489391]

15. Burroughs Wellcome, Research Triangle Park, NC: Personal communication.

16. Sattler FR, Feinberg J. New developments in the treatment of Pneumocystis carinii pneumonia. Chest . 1992; 101:451-7. [PubMed 1531191]

17. Gutteridge WE. 566C80, an antimalarial hydroxynaphthoquinone with broad spectrum: experimental activity against opportunistic parasitic infections of AIDS patients. J Protozool . 1991; 38:141-3S.

18. Fry M, Pudney M. Site of action of the antimalarial hydroxynaphthoquinone, 2-[ trans -4-(4'-chlorophenyl) cyclohexyl]-3-hydroxy-1,4-naphthoquinone (566C80). Biochem Pharmacol . 1992; 43:1545-53. [PubMed 1314606]

20. Burroughs Wellcome. Formulary information: new Mepron^® atovaquone 250 mg tablets. Research Triangle Park, NC; 1992 Nov.

21. Murray JF, Felton CP, Garay SM et al. Pulmonary complications of the acquired immunodeficiency syndrome. Report of a National Heart, Lung, and Blood Institute Workshop. N Engl J Med . 1984; 310:1682-8. [PubMed 6328301]

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23. Anon. New oral agent for PCP is effective, well tolerated. Oncology . 1992; 6:88. [PubMed 1449979]

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26. Dohn MN, Weinberg WG, Torres RA et al. Oral atovaquone compared with intravenous pentamidine for Pneumocystis carinii pneumonia in patients with AIDS. Ann Intern Med . 1994; 121:174-80. [PubMed 7880228]

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28. Hughes W, Leoung G, Kramer F et al. Comparison of 566C80 & trimethoprim-sulfamethoxazole (TMP-SMZ) for the treatment of P. carinii pneumonitis (PCP). Int Conf AIDS 1992. Abstract No. WeB 1019.

30. Pagano G, Kennedy W, Weller S et al. The safety and pharmacokinetics of atovaquone in immunocompromised children. In: Program and Abstracts of the IXth International Conference on AIDS. Berlin, Germany; 1993 June 6-11:378. Abstract No. PO-B10-1455.

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