Atovaquone and Proguanil Hydrochloride

Prevention of Malaria

Prevention (prophylaxis) of malaria caused by Plasmodium falciparum (including chloroquine-resistant P. falciparum).1 5 6 9 10 115 121 134

Recommended by CDC and others as a drug of choice for prophylaxis in those traveling to areas where chloroquine-resistant P. falciparum malaria has been reported;115 121 134 also can be used for prophylaxis in those traveling to areas where chloroquine-resistant P. falciparum has not been reported.115 121 134

Risk of acquiring malaria varies substantially from traveler to traveler and from region to region (even within a single country) because of differences in intensity of malaria transmission within the various regions and season, itinerary, duration, and type of travel.115 121 Malaria transmission occurs in large areas of Africa, Central and South America, parts of the Caribbean, Asia (including South Asia, Southeast Asia, and the Middle East), Eastern Europe, and the South Pacific.115 Mosquito avoidance measures must be used in conjunction with prophylaxis since no drug is 100% effective in preventing malaria.121

Choice of antimalarial for prophylaxis depends on traveler’s risk of acquiring malaria in area(s) visited, risk of exposure to drug-resistant P. falciparum, other medical conditions (e.g., pregnancy), cost, and potential adverse effects.115 121 134

Active only against asexual erythrocytic forms of Plasmodium (not exoerythrocytic stages) and cannot prevent delayed primary attacks or relapse of P. ovale or P. vivax malaria or provide a radical cure;115 134 terminal prophylaxis with 14-day regimen of primaquine may be indicated in addition to mefloquine prophylaxis if travelers were exposed in areas where P. ovale or P. vivax is endemic.115 134

Information on risk of malaria in specific countries and mosquito avoidance measures and recommendations regarding whether prevention of malaria indicated and choice of antimalarials for prevention are available from CDC at and .115

Presumptive Self-treatment of Malaria

Presumptive self-treatment of malaria† in travelers.115 134

In consultation with their health-care provider, some travelers (e.g., those who elect not to use prophylaxis, those who use a prophylaxis regimen that may not have optimal efficacy, those who use effective prophylaxis but will be in very remote areas) may elect to take along an appropriate antimalarial to use for presumptive self-treatment if necessary.115 134

Self-treatment in these situations should be initiated promptly in the event of an influenza-like illness (e.g., fever, chills) if professional medical carenot readily available.115 134

CDC and other experts recommend fixed combination of atovaquone and proguanil (atovaquone/proguanil) or fixed combination of artemether and lumefantrine (artemether/lumefantrine) for presumptive self-treatment of malaria.115 134

Presumptive self-treatment of possible malarial infection is a temporary measure; it is imperative that a professional medical evaluation be obtained as soon as possible.115

Treatment of Uncomplicated Malaria

Treatment of acute, uncomplicated malaria caused by P. falciparum (including chloroquine-resistant P. falciparum)1 7 8 13 14 134 143 or chloroquine-resistant P. vivax†.143

For treatment of uncomplicated malaria caused by chloroquine-resistant P. falciparum or treatment of uncomplicated malaria when plasmodial species not identified, CDC recommends atovaquone/proguanil, artemether/lumefantrine, or regimen of quinine in conjunction with doxycycline, tetracycline, or clindamycin.143 144

For treatment of uncomplicated malaria caused by chloroquine-susceptible P. falciparum, P. malariae, or P. knowlesi or treatment of uncomplicated malaria when plasmodial species not identified and infection acquired in areas where chloroquine resistance not reported, CDC recommends chloroquine (or hydroxychloroquine).143 144 Alternatively, CDC states that any of the regimens recommended for treatment of uncomplicated chloroquine-resistant P. falciparum malaria may be used if preferred, more readily available, or more convenient.143 144

For treatment of uncomplicated malaria caused by chloroquine-resistant P. vivax†, CDC recommends regimen of quinine and doxycycline (or tetracycline) given in conjunction with primaquine, atovaquone/proguanil given in conjunction with primaquine, or mefloquine given in conjunction with primaquine.143 144

Pediatric patients with uncomplicated malaria generally can receive same treatment regimens recommended for adults using age- and weight-appropriate drugs and dosages.143 144 For treatment of uncomplicated chloroquine-resistant P. falciparum in children <8 years of age, atovaquone/proguanil or artemether/lumefantrine usually recommended, but mefloquine can be considered if no other options available.144 For treatment of chloroquine-resistant P. vivax malaria in children <8 years of age, CDC recommends mefloquine given in conjunction with primaquine.143 144 Alternatively, if mefloquine not available or not tolerated and if potential benefits outweigh risks, atovaquone/proguanil or artemether/lumefantrine can be used for treatment of chloroquine-resistant P. vivax in this age group.143 144

Because atovaquone/proguanil active only against asexual erythrocytic forms of Plasmodium (not exoerythrocytic stages), 14-day regimen of primaquine indicated to eradicate hypnozoites and prevent delayed primary attacks or relapse and provide a radical cure whenever atovaquone/proguanil used for treatment of P. ovale or P. vivax malaria.134 143 144

Not indicated for treatment of severe or complicated malaria.1

Assistance with diagnosis or treatment of malaria is available from CDC Malaria Hotline at 770-488-7788 or 855-856-4713 from 9:00 a.m. to 5:00 p.m. Eastern Standard Time or CDC Emergency Operation Center at 770-488-7100 after hours and on weekends and holidays.143 144

Proguanil metabolized principally by CYP2C19; potential pharmacokinetic interactions with drugs that are substrates or inhibitors of CYP2C19.1

Specific Drugs

Absorption

Bioavailability

Oral bioavailability of atovaquone shows considerable interindividual variation;1 absorption of atovaquone may be reduced in patients with diarrhea and vomiting.1

Proguanil hydrochloride extensively absorbed from GI tract.1

Food

Administration with dietary fat increases rate and extent of GI absorption of atovaquone;1 absolute bioavailability is 23% when taken with food.1

Distribution

Extent

Atovaquone distributed into milk in rats; not known whether distributed into human milk.1

Small amounts of proguanil distributed into milk.1

Plasma Protein Binding

Atovaquone >99% bound to plasma proteins; proguanil 75% bound to plasma proteins.1

Elimination

Metabolism

There is indirect evidence that atovaquone may undergo limited metabolism; however, a specific metabolite(s) has not been identified.1 Proguanil metabolized principally by CYP2C19 to the active metabolite cycloguanil and to 4-chlorophenylbiguanide.1

Elimination Route

Following oral administration in healthy individuals, >94% of a dose of atovaquone excreted unchanged in feces; 40–60% of a dose of proguanil excreted in urine.1

Half-life

Atovaquone: Elimination half-life about 2–3 days in adults and 1–2 days in pediatric patients.1

Proguanil: Elimination half-life 12–21 hours in adult and pediatric patients;1 may be longer in slow metabolizers.1

Special Populations

In patients with mild to moderate hepatic impairment, there were no marked differences in rate or extent of systemic exposure to atovaquone, although elimination half-life of atovaquone was prolonged in individuals with moderate hepatic impairment.1 In patients with mild to moderate hepatic impairment, extent of systemic exposure to proguanil was increased and elimination half-life prolonged, with resultant decrease in systemic exposure to cycloguanil and increase in elimination half-life of this metabolite.1

Pharmacokinetics of atovaquone and proguanil in patients with mild renal impairment (Clcr 50–80 mL/minute) similar to that in those with normal renal function.1 In patients with moderate renal impairment (Clcr 30–50 mL/minute), oral clearance of atovaquone unaffected but proguanil oral clearance reduced approximately 35%.1

In patients with severe renal impairment (Clcr <30 mL/minute), systemic exposure to atovaquone was decreased and elimination half-lives of proguanil and cycloguanil were increased, resulting in potential for drug accumulation and toxicity with repeated dosing.1

In geriatric individuals (65–79 years of age), extent of systemic exposure to cycloguanil (active metabolite of proguanil) was increased, and average elimination half-life prolonged (mean: 14.9 hours) compared with younger adults (mean: 8.3 hours).1

• Importance of taking atovaquone/proguanil at same time each day with food or milky drink.1

• Advise patients to repeat a dose if vomiting occurs within 1 hour after ingestion.1

• If a dose is missed, take missed dose as soon as it is remembered.1 If dose is skipped, do not take a double dose to make up for the missed dose.1

• Advise patients of risk of rare serious adverse effects including hepatitis, severe skin reactions, neurologic events, or hematologic events.1

• Importance of consulting a health-care professional regarding other prophylactic regimens if atovaquone/proguanil is discontinued for any reason.1

• Necessity of taking protective measures to reduce contact with mosquitoes (protective clothing, insect repellents, mosquito nets, remaining in air-conditioned or well-screened areas).1 115

• Possibility of contracting malaria during travel, regardless of prophylactic regimen used.1 115

• Importance of seeking medical attention as soon as possible if febrile illness develops during or after return from a malaria-endemic area and of informing clinician of possible malaria exposure, including instances when such illness was self-treated as malaria during travel.1 115

• Advise travelers that presumptive self-treatment of malaria is an interim measure and that they should seek medical evaluation as soon as possible.115

• Importance of informing clinicians of existing or contemplated therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1

• Importance of women informing clinician if they are or plan to become pregnant or plan to breast-feed.1

• Importance of discussing with clinician the risks and benefits of travel to malaria-endemic areas during pregnancy.1 Compared with other populations, pregnant women have higher risk of death and serious complications of falciparum malaria.1

• Importance of advising patients of other important precautionary information.1 (See Cautions.)

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.