Are elevated liver enzymes an adverse side effect of atovaquone-proguanil (Malorone)?/nAn adult mal

Fråga: Are elevated liver enzymes an adverse side effect of atovaquone-proguanil (Malorone)?

An adult male received malaria prophylaxis with atovaquone-proguanil. In this case we have no data of dose, other pharmacological use, liver disease or use of ethanol. After 12 months of treatment the patient has elevated gamma GT (2.20) and after another 4 months (16 months of treatment) the patient also shows elevated ALAT (1.16). Recommended daily dose for malaria prophylaxis in adults is atovaquone 250 mg and proguanil 100 mg.

Sammanfattning: Elevated liver enzymes have been reported as an adverse side effect of atovaquone-proguanil. In the studies mentioned above there was no patient on long term prophylactic treatment.

Svar: Elevated liver enzymes is a known adverse side effect to atovaquone-proguanil (1,2) and to atovaquone alone (3).

In a 3-week study (n=24) of atovaquone treatment (testdoses of 100-3000 mg/day), two patients had slightly raised serum bilirubin concentrations and one each raised transaminase activities. Another two persons with known hep B infections also showed mildly elevated transaminases (4). In another study of 30 Thai children with malaria receiving atovaquone (daily dose 250-750 mg according to bodyweight) and proguanil (daily dose 100-300 mg according to bodyweight) for 3 days, 6.7% (n=2) had elevated ASAT and 10.0% (n=3) had elevated bilirubin (5).

In the Swedish register of adverse drug reactions there are 37 reports on proguanil and 11 on atovaquone. Four reports out of these concerns elevated transaminases, ALP and GT. One case concerns atovaquone-proguanil and three cases concern proguanil in combination with chloroquine (6).

We found one case report of hepatitis during chloroguanide (proguanil) prophylaxis (7). A man was using chloroguanide 200 mg daily for 6 weeks. He was admitted to hospital with jaundice, fever and elevated ALP, ASAT and ALAT. Evaluation of the liver function test result was consistent with cholestatic liver disease, and a toxic reaction to chloroguanide was considered the most likely cause of the clinical presentation. The hepatotoxicity was considered as a combined allergic and idiosyncratic manifestation, thought to be caused by chloroguanide. A biopsy of the liver indicated drug induced hepatitis.

For drug induced hepatitis the abnormality is most likely to occur within 90 days of treatment (8). Fass 2004
Malarone. Drugdex(R) System; Thomson MICROMEDEX, Greenwood Village, Colorado (Edition expires 2003)
Atovaquone. Drugdex(R) System; Thomson MICROMEDEX, Greenwood Village, Colorado (Edition expires 2004)
Dukes MNG, Aronson JK, editor. Meyler´s Side effects of drugs. 14th ed. Amsterdam: Elsevier; 2000. p. 971.

Sabchareon A, Attanath P, Phanuaksook P, Chanthavanich P, Poonpanich Y, et al. Efficacy and pharmacokinetics of atovaquone and proguanil in children with multidrug-resitant Plasmodium falciparum malaria. Trans R Soc Trop Med Hyg 1998;92:201-6. Swedis (cited 2005-01-17) Oostweegel LM, Beijnen JH, Mulder JW. Hepatitis during chloroguanide prophylaxis. Ann Pharmacother 1998;32(10):1023-5. Farrell GC. Drug-induced liver disease. Edinburgh: Churchill Livingstone; 1994. p. 155.