Atovaquone and Proguanil

Atovaquone and proguanil is an antimalarial combination medicine supported across several products for two main uses:

• Prevention of P. falciparum malaria — taken before, during, and after travel to areas where this malaria strain is present, including regions where chloroquine resistance has been reported. Supported by Atovaquone and Proguanil Hydrochloride tablets, Atovaquone and Proguanil Hydrochloride Pediatric tablets, and Malarone tablets.
• Treatment of acute, uncomplicated P. falciparum malaria — a short course to clear an active infection. Supported by the same products listed above, including in areas where chloroquine, mefloquine, halofantrine, and amodiaquine may have unacceptable failure rates due to resistance.

Atovaquone and proguanil work together as a team against the malaria parasite. Atovaquone blocks a key energy-producing process the parasite needs to survive, while proguanil (through its active breakdown product, cycloguanil) interferes with the parasite's ability to make DNA building blocks. Hitting two different targets at once makes it harder for the parasite to develop resistance and increases the medicine's effectiveness.

This combination has shown effectiveness even in areas where other antimalarials have failed, most likely because of established drug resistance to those agents in the local parasite population.

These tablets are taken orally once a day, at the same time each day. Always take them with food or a milky drink — taking atovaquone with fat significantly increases the amount absorbed into your bloodstream. For prevention, start 1–2 days before entering a malaria-risk area and continue daily throughout your stay and for 7 days after you return. For treatment, the course runs for 3 consecutive days. Dose is based on body weight in children.

• If you vomit within one hour of a dose, take a repeat dose
• Tablets may be crushed and mixed with condensed milk right before giving them to someone who has trouble swallowing
• Follow your prescriber's exact instructions — do not adjust the dose or stop early without guidance

Common side effects vary slightly depending on whether you are taking this medicine for prevention or treatment:

• Diarrhea
• Nausea and vomiting
• Abdominal (stomach) pain
• Headache
• Dizziness
• Unusual or vivid dreams
• Mouth sores (oral ulcers)
• Itching (more common in children during treatment)

Serious reactions that need prompt medical attention include severe skin reactions such as widespread blistering or peeling (Stevens-Johnson syndrome), signs of liver problems (yellowing of skin or eyes, severe stomach pain), or a serious allergic reaction (swelling, difficulty breathing). Stop the medicine and seek care right away if any of these occur.

• Severe skin reactions: Life-threatening skin conditions including Stevens-Johnson syndrome (SJS), drug reaction with eosinophilia and systemic symptoms (DRESS), and erythema multiforme have been reported. Stop the medicine immediately and get medical help if a rash, blistering, or mouth sores develop.
• Liver toxicity: Elevated liver tests, hepatitis, and rare cases of liver failure requiring transplantation have been reported with long-term preventive use. Report any yellowing of skin or eyes, dark urine, or unusual fatigue to your doctor.
• Vomiting and diarrhea: These can reduce how much atovaquone is absorbed. If vomiting or diarrhea is severe or persistent, alternative antimalarial treatment may be needed.
• Mixed malaria infections: If you also have a P. vivax infection, this medicine alone often does not prevent P. vivax relapse — additional treatment may be required.
• Treatment failures: If malaria recurs after using this medicine, a different antimalarial agent must be used — not a repeat course of atovaquone and proguanil.
• Not for severe malaria: This medicine has not been tested for cerebral (brain) malaria or other complicated, severe forms of malaria, and is not appropriate when a patient cannot take oral medicines.

Several medicines can affect how well atovaquone and proguanil works, or be affected by it in return:

• Rifampin or rifabutin (antibiotics used for tuberculosis): significantly lower atovaquone blood levels — avoid using these together
• Warfarin and other coumarin-based blood thinners: proguanil may strengthen their blood-thinning effect; clotting tests need close monitoring when starting or stopping this antimalarial
• Tetracycline (an antibiotic): may lower atovaquone levels — parasite levels should be monitored closely if both are needed
• Metoclopramide (a nausea medicine): reduces atovaquone absorption; use only if no other anti-nausea option is available
• Indinavir (an HIV medicine): atovaquone may lower trough levels of indinavir, which could reduce its effectiveness — use with caution

This is not a complete list of interactions. Always talk with your doctor or pharmacist before starting, stopping, or changing any medication.

• Severe kidney disease: Do NOT use this medicine for malaria prevention if your kidney function is severely impaired (creatinine clearance below 30 mL/min). For treatment, use only with extreme caution and only if benefits outweigh the risks.
• Allergy: Do not take if you have ever had a serious allergic reaction (including anaphylaxis, Stevens-Johnson syndrome, or angioedema) to atovaquone, proguanil, or any ingredient in these tablets.
• Pregnancy: Safety data in pregnant women are limited. Malaria during pregnancy is itself dangerous. If you are pregnant or trying to conceive, discuss the risks and benefits with your doctor. Continue folic acid (folate) supplementation as recommended, since proguanil can interfere with folate metabolism.
• Breastfeeding: Proguanil is present in breast milk and atovaquone may be as well. Talk to your doctor before using this medicine while breastfeeding.
• Children: Dosing is based on body weight. Safety and effectiveness for prevention have not been established in children weighing less than 11 kg, and for treatment less than 5 kg.
• Older adults: Use with extra caution — older adults may have reduced kidney or liver function, and drug levels (particularly the active proguanil breakdown product) can be higher than in younger people.
• Mild or moderate kidney impairment: No dose adjustment is needed, but discuss your kidney function with your doctor.
• Mild or moderate liver impairment: No dose adjustment is needed, but no studies have been done in people with severe liver impairment.

There is no known antidote for atovaquone overdose, and it is not known whether dialysis removes it from the body. Reported overdoses of atovaquone have included rash, and in one case involving another drug taken at the same time, a blood condition called methemoglobinemia (reduced ability of red blood cells to carry oxygen) occurred. Proguanil overdoses have generally been followed by full recovery, but may cause stomach discomfort, vomiting, reversible hair loss, skin peeling on the palms or soles, and blood abnormalities. If you suspect an overdose, contact a poison control center or emergency services right away.

The effect of atovaquone and proguanil tablets on the QT interval — a measure of heart electrical activity — is not known in humans. The lower doses used for prevention were generally better tolerated than the higher doses used for treatment. Both components act directly against the malaria parasite rather than through effects on human body systems.

Atovaquone is a highly fat-soluble compound, and its absorption varies considerably from person to person — taking it with food or a fatty drink can increase the amount absorbed by 2 to 3 times. Atovaquone stays in the body for a long time, with a half-life (the time for half the drug to leave the body) of about 2–3 days in adults and 1–2 days in children; it is mostly excreted unchanged in the stool with very little leaving through the urine. Proguanil is processed mainly by the liver (via a liver enzyme called CYP2C19) into its active form, cycloguanil, and leaves the body more quickly with a half-life of 12–21 hours; 40–60% is excreted by the kidneys. In people with moderate or severe kidney disease, proguanil clearance is reduced, which can increase drug exposure; in older adults, levels of the active proguanil breakdown product are also higher than in younger people.

Store at 25oC (77oF); excursions permitted to 15o to 30oC (59o to 86oF) (see USP Controlled Room Temperature).