Limitations: This safety classification applies only to preparations containing a combination of the two drugs proguanil and atovaquone. This ATC-code (P01BB51) may in some countries be used for different combinations of proguanil and other drugs which in theory may be porphyrinogenic. Please refer to the classification and monograph of each individual substance. If the combination contains a substance which is not classified (NC) or has been classified as porphyrinogenic (PRP or P), the safety classification of such a combination as PNP is no longer valid. Atovaquone is excreted unmetabolized. Proguanil may be a weak inhibitor of CYP 2C9. None of the two drugs seem to have significant capacities for CYP-induction or irreversible CYP-inhibition. There are no pharmacodynamic effects or side effects of relevance to activation of acute porphyria. There are 6 and 8 reports, respectively, of safe use of atovaquone and proguanil

Proguanil: Chlorophenyl isopropyl biguanide hydrochloride Atovaquone: Chlorophenyl cyclohexyl hydroxynaphtaquinone

The combination of proguanil and atovaquone is used in the treatment and prophylaxis against malaria (P. Falciparum, P. Vivax). It is administered orally. Common adverse reactions of proguanil and atovaquone that can be confused with an acute porphyric attack are abdominal pain, nausea, vomiting and diarrhoea.

Atovaquone: Almost quantitatively (>90 %) excreted unchanged in faeces. Proguanil: Weak substrate of CYP3A4, but no in vitro observations of CYP3A4 inhibition or induction reported, nor any effects on P-gp activity (Zhou et al 2007). Reported to be a weak and clinically insignificant inhibitor of CYP2D6 (Bapiro 2001). Less than 40 per cent is metabolized by CYP2C19 and CYP1A2 to the active cycloguanile metabolite and to a lesser extent to chlorphenyl biguanide, which both are excreted unchanged in urine. There are no results of systematic interaction studies reported, but there is one recent observation of increase of the plasma concentration of saquinavir under co-medication with atovaquone/proguanil, drug interference suggested to be CYP-related, possibly by inhibition of CYP 2C isoenzymes (Tommasi 2011). Miller (2002) found atovaquone to be an in vitro inhibitor of CYP 2C9. In spite of the fairy long use of the drugs there are no other reports of pharmacokinetic CYP-engaged drug-interactions. There are no observations of accumulation of the drugs or of therapeutic failure in long term use, and there are no observations of organotoxic effects, which speak against capacity of the combination for significant irreversible CYP-inhibition.

Uneventful use reported in 2 patients with acute porphyria.