The Quinism Foundation Calls on the CDC to Update its Malaria Prevention Recommendations to Reflect Important FDA Safety Warnings for Tafenoquine and Mefloquine

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The Foundation Warns that Psychiatric Symptoms Including Insomnia, Abnormal Dreams, and Nightmares Should be Considered Prodromal to More Serious Adverse Effects

The Quinism Foundation has sent correspondence to Dr. Robert R. Redfield, Director of the Centers for Disease Control and Prevention (CDC) calling on its Division of Global Migration and Quarantine to emphasize important safety warnings in the approved U.S. drug labels for tafenoquine and mefloquine. The foundation is requesting that these warnings be reflected in the Division’s Travelers’ Health products and publications, including CDC’s Health Information for International Travel (the "Yellow Book"), particularly as recommendations for use of tafenoquine for prevention of malaria are added to this material.

Tafenoquine was recently approved by the U.S. Food and Drug Administration (FDA) for the prevention of malaria and will be marketed for this indication by 60 Degrees Pharmaceuticals under the brand name Arakoda™.

"It is the position of The Quinism Foundation that, as with mefloquine, while taking tafenoquine for the prevention of malaria, any psychiatric symptoms that develop including symptoms as seemingly mild as insomnia, abnormal dreams, or nightmares, should be considered prodromal to more serious adverse effects," said Remington Nevin, MD, MPH, DrPH, executive director of The Quinism Foundation. "This position appears to be echoed in warnings in the FDA-approved U.S. labeling for tafenoquine, which advises patients to be 'promptly evaluated by a medical professional' should psychiatric symptoms such as insomnia, abnormal dreams, anxiety, or changes in mood be severe, or continue for 3 days or longer while taking the drug."

In its correspondence, Dr. Nevin noted The Quinism Foundation's concerns that unless these warnings are properly emphasized in CDC's recommendations, that these may be overlooked by travel medicine practitioners, as similar warnings for use of mefloquine were overlooked years earlier.

"We recommend that prescribers schedule a visit with the patient prior to travel, to assess for the development of psychiatric symptoms following administration of the tafenoquine loading dose. Access to healthcare, as recommended in the FDA-approved U.S. tafenoquine drug label, may be limited once travel begins," said Dr. Nevin. "We also recommend that tafenoquine should not be prescribed prior to sleep-disrupting travel across time zones, to which insomnia as a side effect of tafenoquine may be misattributed. In addition, tafenoquine should not be prescribed with hypnotics or other sleep-aids, which may confound recognition of insomnia as a side effect.”

“Other psychiatric side effects of tafenoquine, including changes in mood, anxiety, abnormal dreams or nightmares, may similarly risk being misattributed to the effects of certain forms of travel, including military deployments and travel for humanitarian emergencies and disaster response. Tafenoquine should not be prescribed prior to such travel, as this may similarly confound recognition of such side effects.”

"As with mefloquine, we also recommend that tafenoquine should not be prescribed for travelers with existing psychiatric symptoms or disorders.”

"Publicly-available data support a conclusion that tafenoquine shares the liability to central nervous system (CNS) neurotoxicity of mefloquine," said Dr. Nevin. "In a randomized blinded trial of tafenoquine in comparison to mefloquine for prophylaxis, users of tafenoquine reported a comparable rate of neuropsychiatric symptoms as users of mefloquine." [1]

"However, in comparison to data from the most recent Cochrane review of mefloquine in comparison to the non-neurotoxic alternative, atovaquone-proguanil, for prevention of malaria, there is clear evidence of under-reporting of neuropsychiatric adverse effects from mefloquine in this trial." [2]

"Assuming equal underreporting in each arm, as would be expected in a randomized blinded trial, and adjusting for such apparent underreporting, symptoms of anxiety and depression would be expected to be 'common' with use of tafenoquine for prophylaxis, occurring in 1-10% of users. Similarly, symptoms of abnormal dreams and insomnia would be expected to be 'very common', occurring in greater than 10% of users. As with mefloquine, tafenoquine has also been reported to be associated with reports of psychosis and other more 'severe' and 'serious' neuropsychiatric adverse effects, which may occur with continued use of the drug after prodromal symptoms occur."

"Given the new availability of tafenoquine," said Dr. Nevin, "we are asking that CDC update its recommendations for the use of mefloquine to align with those of international militaries and a growing number of other countries’ civilian travel advisory bodies, by declaring mefloquine a 'drug of last resort' for prevention of malaria among healthy adult travelers. We are also asking that CDC reconsider its recommendations for use of the drug in pregnant women, and in pre-verbal infants and children, among whom current U.S. drug label guidance creates challenges for the appropriate use of this medication."

Dr. Nevin noted that although mefloquine continues to be recommended by the CDC for pregnant women, infants and children, the development of prodromal symptoms in pre-verbal infants and children and in the developing fetus cannot be reliably identified and acted on in accordance with the FDA-approved U.S. mefloquine drug label.

"The U.S. mefloquine drug label warns that psychiatric symptoms should require the drug's discontinuation," said Dr. Nevin. "Although a pregnant mother, or mother traveling with her pre-verbal child may herself tolerate mefloquine, she cannot exclude the possibility her developing fetus or pre-verbal child may be experiencing psychiatric symptoms, including abnormal dreams or nightmares, which would require the drug's discontinuation in an adult traveler."

About The Quinism Foundation

The Quinism Foundation, founded in January 2018, in White River Junction, Vermont, promotes and supports education and research on quinism, the family of medical disorders caused by poisoning by quinoline drugs, including mefloquine and tafenoquine.

Executive director Dr. Nevin is a board-certified occupational medicine and preventive medicine physician and former U.S. Army medical officer and epidemiologist. He is author of more than 30 scientific publications on malaria and the quinoline antimalarials.

1. Nasveld PE et al. Randomized, double-blind study of the safety, tolerability, and efficacy of tafenoquine versus mefloquine for malaria prophylaxis in nonimmune subjects. Antimicrobial Agents and Chemotherapy. 2010; 54(2), 792–798.

2. Tickell-Painter M et al. Mefloquine for preventing malaria during travel to endemic areas. The Cochrane database of systematic reviews. 2017;10(10):CD006491.

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