Is atovaquone (Malarone) and proguanil safe in patients with Glucose-6-phosphate dehydrogenase (G6PD) deficiency and liver impairment, with elevated liver enzymes and hyperbilirubinemia, suspected of having severe malaria?

Safety of Atovaquone-Proguanil in G6PD Deficiency and Liver Impairment

Atovaquone-proguanil is generally safe in G6PD deficiency but should be avoided in severe liver impairment with significantly elevated liver enzymes and hyperbilirubinemia as seen in this case of suspected severe malaria.

Safety in G6PD Deficiency

Atovaquone-proguanil is considered safe for patients with G6PD deficiency:

• Unlike primaquine and other 8-aminoquinolines, atovaquone-proguanil does not cause hemolysis in G6PD-deficient individuals 1
• There are no specific warnings or contraindications regarding G6PD deficiency in the FDA drug labeling for atovaquone or proguanil 2, 3
• G6PD testing is primarily required before administering primaquine (for radical cure of P. vivax/P. ovale) rather than for atovaquone-proguanil therapy 1, 4

Concerns in Liver Impairment

However, there are significant concerns about using atovaquone-proguanil in patients with liver impairment:

• The FDA labeling for atovaquone warns that "cases of cholestatic hepatitis, elevated liver enzymes, and fatal liver failure have been reported in patients treated with atovaquone" 3
• The FDA labeling for proguanil notes "elevated liver function tests and rare cases of hepatitis have been reported with prophylactic use of atovaquone and proguanil hydrochloride. A single case of hepatic failure requiring liver transplantation has also been reported" 2
• The drug labeling specifically cautions that patients with severe hepatic impairment should be closely monitored following administration of atovaquone 3

Assessment of Current Case

In this case, the patient has:

• Suspected severe malaria
• Significantly elevated liver enzymes (2× normal)
• Markedly elevated total bilirubin (15 mg/dL)
• Both direct (7.5 mg/dL) and indirect (8.44 mg/dL) hyperbilirubinemia

These findings indicate:

1. Severe liver dysfunction
2. Possible hemolysis (elevated indirect bilirubin)
3. Possible cholestasis (elevated direct bilirubin)

Recommendations for Treatment

Given these findings:

1. Avoid atovaquone-proguanil in this patient due to the severe liver impairment
2. For severe malaria, intravenous artesunate is the first-line treatment recommended by guidelines 5
3. Artesunate should be administered at 2.4 mg/kg IV at 0,12, and 24 hours, then daily for up to 7 days 5
4. If artesunate is unavailable, intravenous quinine is the second-line alternative 5

Alternative Treatment Options

If IV artesunate is not available:

• IV quinine dihydrochloride: 20 mg salt/kg loading dose over 4 hours, followed by 10 mg/kg over 4 hours starting 8 hours after initiation, then every 8 hours 5
• Switch to oral therapy only when clinically improved and able to tolerate oral medications 5

Monitoring Recommendations

• Close monitoring of liver function tests
• Serial monitoring of bilirubin levels (both direct and indirect)
• Parasitemia monitoring every 12-24 hours until clearance
• Monitor for signs of hemolysis, especially if G6PD status is unknown
• Monitor for hypoglycemia, particularly if quinine is used 5

Key Considerations

• Atovaquone-proguanil is contraindicated for treatment of severe malaria regardless of liver function, as stated in the FDA labeling: "Atovaquone and proguanil hydrochloride has not been evaluated for the treatment of cerebral malaria or other severe manifestations of complicated malaria, including hyperparasitemia, pulmonary edema, or renal failure. Patients with severe malaria are not candidates for oral therapy" 2

• While atovaquone-proguanil is safe in G6PD deficiency, the current clinical presentation suggests both severe malaria and significant liver dysfunction, making parenteral therapy with artesunate the appropriate choice 5