Timing, adverse effects are factors in choosing malaria prophylaxis

January 2005

Although no chemoprophylaxis regimen for malaria is 100% effective, today’s travel medicine physician is fortunate to have a choice of four drugs to prescribe to the traveler with confidence.

“The four FDA-approved drugs for malaria prophylaxis are mefloquine, atovaquone-proguanil [Malarone, GlaxoSmithKline], chloroquine and doxycycline. Another drug, primaquine, can be used for special populations, but it does not have an FDA-approved indication for prophylaxis,” said Alan J. Magill, MD, science director of the Walter Reed Army Institute of Research in Silver Spring, Md.

“Awareness and knowledge of the risk of malaria by both the patient and the physician is important,” said Magill at the 53rd Annual Meeting of the American Society of Tropical Medicine and Hygiene meeting in Miami. “Conscientious use of personal protection measures and compliance with the prescribed chemoprophylaxis regimen will prevent the vast majority of malaria cases. When all else fails, prompt diagnosis and early treatment will likely render malaria a relatively benign febrile illness.”

Nearly all malaria cases in the United States and Canada can be attributed to the lack of chemoprophylaxis, prescription of incorrect agents or lack of adherence to the prescribed regimen by the traveler.

The three drugs available to prevent choloroquine-resistant Plasmodium falciparum malaria are atovaquone-proguanil, mefloquine and doxycycline. All are efficacious, and the CDC currently does not have a recommended drug of choice. Instead, the choice is made based on the tolerability of a particular agent in the individual traveler.

Mefloquine

Mefloquine is taken once a week and is also now available generically, “so the cost is somewhat less than Lariam [Hoffman-La Roche]. But other people may already be taking a daily drug, such as aspirin or a statin, so adding another daily drug like doxycycline to their regimen may not be an inconvenience at all,” Magill said.

Magill noted that outside of a few areas along the Thailand-Myanmar and Thailand-Cambodian borders, mefloquine resistance is not a factor in choosing a chemoprophylactic agent. Although the drug remains highly efficacious, neuropsychiatric and gastrointestinal (GI) adverse effects are a concern. “One study found that 5% of patients discontinued use of mefloquine because of an adverse event vs. 1.2% for atovaquone-proguanil,” Magill said.

Major product label revisions for Lariam occurred in October 2002. “Warning sections were expanded for psychiatric disorders and symptoms,” Magill said. “I encourage anyone prescribing mefloquine to visit the FDA Web site, where FDA letters and label updates can easily be downloaded.”

Prescribing mefloquine today can be a challenge, in part because of recommended restrictions for patients with depression and generalized anxiety disorders. “Sleep disturbances and a mild dizziness or vertigo are not uncommon,” Magill said. “It can also be difficult to distinguish any adverse event to a malaria drug because of the travel-associated symptoms such as jet lag and common disorders such as traveler’s diarrhea.”

On the other hand, many individuals tolerate mefloquine without problems, and it remains a convenient and cost-effective choice.

Controversy lingers over when a person should start mefloquine prior to travel. “The prescribed regimen is one to two weeks in advance, but some practices begin three or four weeks beforehand to help predict adverse events,” Magill said. “In any event, you do need to continue medication four weeks after travel.”

For patients intolerant of mefloquine, “I would move quickly to either atovaquone-proguanil or doxycycline,” Magill said. “Doxycycline is a very useful choice for us today, and it is very efficacious. Eight randomized trials show that the drug works. I think the big issue for most travelers is GI tolerance, if the drug is not taken correctly.” Magill recommended taking doxycycline in the morning, upright, with a full glass of water and breakfast. This way, the drug is generally well tolerated by most individuals.

Randomized, controlled trials suggest that doxycycline is better tolerated than mefloquine and as well tolerated as atovaquone-proguanil. That said, “effectiveness remains an issue as very few people will actually take doxycycline for the recommended 28 days after travel,” Magill said. “But you don’t need to worry about resistance as a factor or criterion for prescribing.” Doxycycline, also a broad-spectrum antibiotic, is an efficacious prophylactic for rickettsial infections and leptospirosis as well.

On the downside, there are drug-drug interactions with doxycycline. Tooth and enamel discoloration may also occur in those younger than 8 years, so the drug should not be prescribed for children and nursing women. Using sunblock is also advised because doxycycline is a photosensitizing agent.

Atovaquone-proguanil

Atovaquone-proguanil, the newest of the approved drugs, “is taken once daily and is very efficacious and very well tolerated,” Magill said.

Travelers can begin the drug one or two days before travel, during travel and is needed for only seven days after travel. “Cost can be an issue, however, especially for a trip lasting longer than two to three weeks. But for short-term travel, atovaquone-proguanil is very well tolerated and cost neutral compared to the other choices,” he said.

“Prompt diagnosis and early oral treatment almost always leads to a good outcome for malaria,” Magill concluded. “In contrast, a delayed diagnosis, IV therapy and admission to the ICU will be a very bad day for everyone involved.”

For more information:

• Magill AJ. The state of the art in malaria prophylaxis in the traveler. Presented at the 53rd Annual Meeting of the American Society of Tropical Medicine and Hygiene. Nov. 7-11, 2004. Miami.