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Suggested Citation:"4 Mefloquine." National Academies of Sciences, Engineering, and Medicine. 2020. Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis. Washington, DC: The National Academies Press. doi: 10.17226/25688.
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Suggested Citation:"4 Mefloquine." National Academies of Sciences, Engineering, and Medicine. 2020. Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis. Washington, DC: The National Academies Press. doi: 10.17226/25688.
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Suggested Citation:"4 Mefloquine." National Academies of Sciences, Engineering, and Medicine. 2020. Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis. Washington, DC: The National Academies Press. doi: 10.17226/25688.
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Suggested Citation:"4 Mefloquine." National Academies of Sciences, Engineering, and Medicine. 2020. Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis. Washington, DC: The National Academies Press. doi: 10.17226/25688.
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Suggested Citation:"4 Mefloquine." National Academies of Sciences, Engineering, and Medicine. 2020. Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis. Washington, DC: The National Academies Press. doi: 10.17226/25688.
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Suggested Citation:"4 Mefloquine." National Academies of Sciences, Engineering, and Medicine. 2020. Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis. Washington, DC: The National Academies Press. doi: 10.17226/25688.
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Suggested Citation:"4 Mefloquine." National Academies of Sciences, Engineering, and Medicine. 2020. Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis. Washington, DC: The National Academies Press. doi: 10.17226/25688.
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Suggested Citation:"4 Mefloquine." National Academies of Sciences, Engineering, and Medicine. 2020. Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis. Washington, DC: The National Academies Press. doi: 10.17226/25688.
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Suggested Citation:"4 Mefloquine." National Academies of Sciences, Engineering, and Medicine. 2020. Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis. Washington, DC: The National Academies Press. doi: 10.17226/25688.
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Suggested Citation:"4 Mefloquine." National Academies of Sciences, Engineering, and Medicine. 2020. Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis. Washington, DC: The National Academies Press. doi: 10.17226/25688.
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Suggested Citation:"4 Mefloquine." National Academies of Sciences, Engineering, and Medicine. 2020. Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis. Washington, DC: The National Academies Press. doi: 10.17226/25688.
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Suggested Citation:"4 Mefloquine." National Academies of Sciences, Engineering, and Medicine. 2020. Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis. Washington, DC: The National Academies Press. doi: 10.17226/25688.
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Suggested Citation:"4 Mefloquine." National Academies of Sciences, Engineering, and Medicine. 2020. Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis. Washington, DC: The National Academies Press. doi: 10.17226/25688.
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Suggested Citation:"4 Mefloquine." National Academies of Sciences, Engineering, and Medicine. 2020. Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis. Washington, DC: The National Academies Press. doi: 10.17226/25688.
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Suggested Citation:"4 Mefloquine." National Academies of Sciences, Engineering, and Medicine. 2020. Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis. Washington, DC: The National Academies Press. doi: 10.17226/25688.
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Suggested Citation:"4 Mefloquine." National Academies of Sciences, Engineering, and Medicine. 2020. Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis. Washington, DC: The National Academies Press. doi: 10.17226/25688.
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Suggested Citation:"4 Mefloquine." National Academies of Sciences, Engineering, and Medicine. 2020. Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis. Washington, DC: The National Academies Press. doi: 10.17226/25688.
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Suggested Citation:"4 Mefloquine." National Academies of Sciences, Engineering, and Medicine. 2020. Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis. Washington, DC: The National Academies Press. doi: 10.17226/25688.
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Suggested Citation:"4 Mefloquine." National Academies of Sciences, Engineering, and Medicine. 2020. Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis. Washington, DC: The National Academies Press. doi: 10.17226/25688.
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Suggested Citation:"4 Mefloquine." National Academies of Sciences, Engineering, and Medicine. 2020. Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis. Washington, DC: The National Academies Press. doi: 10.17226/25688.
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Suggested Citation:"4 Mefloquine." National Academies of Sciences, Engineering, and Medicine. 2020. Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis. Washington, DC: The National Academies Press. doi: 10.17226/25688.
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Suggested Citation:"4 Mefloquine." National Academies of Sciences, Engineering, and Medicine. 2020. Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis. Washington, DC: The National Academies Press. doi: 10.17226/25688.
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Suggested Citation:"4 Mefloquine." National Academies of Sciences, Engineering, and Medicine. 2020. Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis. Washington, DC: The National Academies Press. doi: 10.17226/25688.
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Suggested Citation:"4 Mefloquine." National Academies of Sciences, Engineering, and Medicine. 2020. Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis. Washington, DC: The National Academies Press. doi: 10.17226/25688.
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Suggested Citation:"4 Mefloquine." National Academies of Sciences, Engineering, and Medicine. 2020. Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis. Washington, DC: The National Academies Press. doi: 10.17226/25688.
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Suggested Citation:"4 Mefloquine." National Academies of Sciences, Engineering, and Medicine. 2020. Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis. Washington, DC: The National Academies Press. doi: 10.17226/25688.
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Suggested Citation:"4 Mefloquine." National Academies of Sciences, Engineering, and Medicine. 2020. Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis. Washington, DC: The National Academies Press. doi: 10.17226/25688.
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Suggested Citation:"4 Mefloquine." National Academies of Sciences, Engineering, and Medicine. 2020. Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis. Washington, DC: The National Academies Press. doi: 10.17226/25688.
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Suggested Citation:"4 Mefloquine." National Academies of Sciences, Engineering, and Medicine. 2020. Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis. Washington, DC: The National Academies Press. doi: 10.17226/25688.
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Suggested Citation:"4 Mefloquine." National Academies of Sciences, Engineering, and Medicine. 2020. Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis. Washington, DC: The National Academies Press. doi: 10.17226/25688.
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Suggested Citation:"4 Mefloquine." National Academies of Sciences, Engineering, and Medicine. 2020. Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis. Washington, DC: The National Academies Press. doi: 10.17226/25688.
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Suggested Citation:"4 Mefloquine." National Academies of Sciences, Engineering, and Medicine. 2020. Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis. Washington, DC: The National Academies Press. doi: 10.17226/25688.
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Suggested Citation:"4 Mefloquine." National Academies of Sciences, Engineering, and Medicine. 2020. Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis. Washington, DC: The National Academies Press. doi: 10.17226/25688.
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Suggested Citation:"4 Mefloquine." National Academies of Sciences, Engineering, and Medicine. 2020. Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis. Washington, DC: The National Academies Press. doi: 10.17226/25688.
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Suggested Citation:"4 Mefloquine." National Academies of Sciences, Engineering, and Medicine. 2020. Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis. Washington, DC: The National Academies Press. doi: 10.17226/25688.
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Suggested Citation:"4 Mefloquine." National Academies of Sciences, Engineering, and Medicine. 2020. Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis. Washington, DC: The National Academies Press. doi: 10.17226/25688.
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Suggested Citation:"4 Mefloquine." National Academies of Sciences, Engineering, and Medicine. 2020. Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis. Washington, DC: The National Academies Press. doi: 10.17226/25688.
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Suggested Citation:"4 Mefloquine." National Academies of Sciences, Engineering, and Medicine. 2020. Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis. Washington, DC: The National Academies Press. doi: 10.17226/25688.
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Suggested Citation:"4 Mefloquine." National Academies of Sciences, Engineering, and Medicine. 2020. Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis. Washington, DC: The National Academies Press. doi: 10.17226/25688.
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Suggested Citation:"4 Mefloquine." National Academies of Sciences, Engineering, and Medicine. 2020. Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis. Washington, DC: The National Academies Press. doi: 10.17226/25688.
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Suggested Citation:"4 Mefloquine." National Academies of Sciences, Engineering, and Medicine. 2020. Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis. Washington, DC: The National Academies Press. doi: 10.17226/25688.
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Suggested Citation:"4 Mefloquine." National Academies of Sciences, Engineering, and Medicine. 2020. Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis. Washington, DC: The National Academies Press. doi: 10.17226/25688.
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Suggested Citation:"4 Mefloquine." National Academies of Sciences, Engineering, and Medicine. 2020. Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis. Washington, DC: The National Academies Press. doi: 10.17226/25688.
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Suggested Citation:"4 Mefloquine." National Academies of Sciences, Engineering, and Medicine. 2020. Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis. Washington, DC: The National Academies Press. doi: 10.17226/25688.
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Suggested Citation:"4 Mefloquine." National Academies of Sciences, Engineering, and Medicine. 2020. Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis. Washington, DC: The National Academies Press. doi: 10.17226/25688.
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Suggested Citation:"4 Mefloquine." National Academies of Sciences, Engineering, and Medicine. 2020. Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis. Washington, DC: The National Academies Press. doi: 10.17226/25688.
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Suggested Citation:"4 Mefloquine." National Academies of Sciences, Engineering, and Medicine. 2020. Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis. Washington, DC: The National Academies Press. doi: 10.17226/25688.
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Suggested Citation:"4 Mefloquine." National Academies of Sciences, Engineering, and Medicine. 2020. Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis. Washington, DC: The National Academies Press. doi: 10.17226/25688.
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Suggested Citation:"4 Mefloquine." National Academies of Sciences, Engineering, and Medicine. 2020. Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis. Washington, DC: The National Academies Press. doi: 10.17226/25688.
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Suggested Citation:"4 Mefloquine." National Academies of Sciences, Engineering, and Medicine. 2020. Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis. Washington, DC: The National Academies Press. doi: 10.17226/25688.
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Suggested Citation:"4 Mefloquine." National Academies of Sciences, Engineering, and Medicine. 2020. Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis. Washington, DC: The National Academies Press. doi: 10.17226/25688.
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Suggested Citation:"4 Mefloquine." National Academies of Sciences, Engineering, and Medicine. 2020. Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis. Washington, DC: The National Academies Press. doi: 10.17226/25688.
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Suggested Citation:"4 Mefloquine." National Academies of Sciences, Engineering, and Medicine. 2020. Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis. Washington, DC: The National Academies Press. doi: 10.17226/25688.
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Suggested Citation:"4 Mefloquine." National Academies of Sciences, Engineering, and Medicine. 2020. Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis. Washington, DC: The National Academies Press. doi: 10.17226/25688.
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Suggested Citation:"4 Mefloquine." National Academies of Sciences, Engineering, and Medicine. 2020. Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis. Washington, DC: The National Academies Press. doi: 10.17226/25688.
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Suggested Citation:"4 Mefloquine." National Academies of Sciences, Engineering, and Medicine. 2020. Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis. Washington, DC: The National Academies Press. doi: 10.17226/25688.
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Suggested Citation:"4 Mefloquine." National Academies of Sciences, Engineering, and Medicine. 2020. Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis. Washington, DC: The National Academies Press. doi: 10.17226/25688.
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Suggested Citation:"4 Mefloquine." National Academies of Sciences, Engineering, and Medicine. 2020. Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis. Washington, DC: The National Academies Press. doi: 10.17226/25688.
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Suggested Citation:"4 Mefloquine." National Academies of Sciences, Engineering, and Medicine. 2020. Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis. Washington, DC: The National Academies Press. doi: 10.17226/25688.
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Suggested Citation:"4 Mefloquine." National Academies of Sciences, Engineering, and Medicine. 2020. Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis. Washington, DC: The National Academies Press. doi: 10.17226/25688.
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Suggested Citation:"4 Mefloquine." National Academies of Sciences, Engineering, and Medicine. 2020. Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis. Washington, DC: The National Academies Press. doi: 10.17226/25688.
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Suggested Citation:"4 Mefloquine." National Academies of Sciences, Engineering, and Medicine. 2020. Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis. Washington, DC: The National Academies Press. doi: 10.17226/25688.
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Suggested Citation:"4 Mefloquine." National Academies of Sciences, Engineering, and Medicine. 2020. Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis. Washington, DC: The National Academies Press. doi: 10.17226/25688.
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Suggested Citation:"4 Mefloquine." National Academies of Sciences, Engineering, and Medicine. 2020. Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis. Washington, DC: The National Academies Press. doi: 10.17226/25688.
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Suggested Citation:"4 Mefloquine." National Academies of Sciences, Engineering, and Medicine. 2020. Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis. Washington, DC: The National Academies Press. doi: 10.17226/25688.
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Suggested Citation:"4 Mefloquine." National Academies of Sciences, Engineering, and Medicine. 2020. Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis. Washington, DC: The National Academies Press. doi: 10.17226/25688.
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Suggested Citation:"4 Mefloquine." National Academies of Sciences, Engineering, and Medicine. 2020. Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis. Washington, DC: The National Academies Press. doi: 10.17226/25688.
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Suggested Citation:"4 Mefloquine." National Academies of Sciences, Engineering, and Medicine. 2020. Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis. Washington, DC: The National Academies Press. doi: 10.17226/25688.
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Suggested Citation:"4 Mefloquine." National Academies of Sciences, Engineering, and Medicine. 2020. Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis. Washington, DC: The National Academies Press. doi: 10.17226/25688.
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Suggested Citation:"4 Mefloquine." National Academies of Sciences, Engineering, and Medicine. 2020. Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis. Washington, DC: The National Academies Press. doi: 10.17226/25688.
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Suggested Citation:"4 Mefloquine." National Academies of Sciences, Engineering, and Medicine. 2020. Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis. Washington, DC: The National Academies Press. doi: 10.17226/25688.
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Suggested Citation:"4 Mefloquine." National Academies of Sciences, Engineering, and Medicine. 2020. Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis. Washington, DC: The National Academies Press. doi: 10.17226/25688.
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Suggested Citation:"4 Mefloquine." National Academies of Sciences, Engineering, and Medicine. 2020. Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis. Washington, DC: The National Academies Press. doi: 10.17226/25688.
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Suggested Citation:"4 Mefloquine." National Academies of Sciences, Engineering, and Medicine. 2020. Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis. Washington, DC: The National Academies Press. doi: 10.17226/25688.
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Suggested Citation:"4 Mefloquine." National Academies of Sciences, Engineering, and Medicine. 2020. Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis. Washington, DC: The National Academies Press. doi: 10.17226/25688.
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Suggested Citation:"4 Mefloquine." National Academies of Sciences, Engineering, and Medicine. 2020. Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis. Washington, DC: The National Academies Press. doi: 10.17226/25688.
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Suggested Citation:"4 Mefloquine." National Academies of Sciences, Engineering, and Medicine. 2020. Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis. Washington, DC: The National Academies Press. doi: 10.17226/25688.
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Suggested Citation:"4 Mefloquine." National Academies of Sciences, Engineering, and Medicine. 2020. Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis. Washington, DC: The National Academies Press. doi: 10.17226/25688.
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Suggested Citation:"4 Mefloquine." National Academies of Sciences, Engineering, and Medicine. 2020. Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis. Washington, DC: The National Academies Press. doi: 10.17226/25688.
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Suggested Citation:"4 Mefloquine." National Academies of Sciences, Engineering, and Medicine. 2020. Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis. Washington, DC: The National Academies Press. doi: 10.17226/25688.
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Suggested Citation:"4 Mefloquine." National Academies of Sciences, Engineering, and Medicine. 2020. Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis. Washington, DC: The National Academies Press. doi: 10.17226/25688.
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Suggested Citation:"4 Mefloquine." National Academies of Sciences, Engineering, and Medicine. 2020. Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis. Washington, DC: The National Academies Press. doi: 10.17226/25688.
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Suggested Citation:"4 Mefloquine." National Academies of Sciences, Engineering, and Medicine. 2020. Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis. Washington, DC: The National Academies Press. doi: 10.17226/25688.
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Suggested Citation:"4 Mefloquine." National Academies of Sciences, Engineering, and Medicine. 2020. Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis. Washington, DC: The National Academies Press. doi: 10.17226/25688.
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Suggested Citation:"4 Mefloquine." National Academies of Sciences, Engineering, and Medicine. 2020. Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis. Washington, DC: The National Academies Press. doi: 10.17226/25688.
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Suggested Citation:"4 Mefloquine." National Academies of Sciences, Engineering, and Medicine. 2020. Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis. Washington, DC: The National Academies Press. doi: 10.17226/25688.
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4 Mefloquine In the late 1960s mefloquine hydrochloride—more commonly known simply as mefloquine—was developed by Walter Reed Army Institute as part of the U.S. Army Antimalarial Drug Development Project. Phase I human tolerance and safety testing for the treatment of malaria began in 1972, and the first trials for its use as a prophylactic occurred in 1976 (Shanks, 1994). In 1976 a collaboration was formed with the U.S. Army, the World Health Organization (WHO), and Hoffmann-La Roche (the manufacturer) to further develop mefloquine. Mefloquine (trade name Lariam®) was first introduced to the market in February 1984 (Adamcova et al., 2015) and became generally available for European travelers in 1985 (Heimgartner, 1986). A new drug application for it was submitted to the Food and Drug Administration (FDA) in 1986 and it was approved in 1989. The mefloquine dosing regimen for malaria prophylaxis begins with taking one tablet (250 mg salt in the United States or 228 mg base) once a week, starting two weeks prior to arriving in an endemic area, taking mefloquine weekly (allowing no more than 8 days to elapse) while in the endemic area, and continuing it for 4 weeks after leaving the endemic area (CDC, n.d.). The once-per-week regimen is perceived to be convenient and is preferred for many individuals, such as long-term travelers and military personnel, as it reduces the amount of medication people have to carry and may require less vigilance to correctly adhere to prescription guidelines than daily malaria prophylactic drugs (e.g., doxycycline, primaquine, atovaquone/ proguanil [A/P]) (Adshead, 2014). Soon after mefloquine entered the market, reports of associated adverse events, specifically neuropsychiatric in nature, began to be reported to FDA and coincided with increased attention from the media about possible side effects (Croft, 2007). This led to several reassessments that included more recent epidemiologic and 91

92 LONG-TERM HEALTH EFFECTS OF ANTIMALARIAL DRUGS t ­oxicologic evidence and resulted in updates to the FDA label over time. Ques- tions and concerns about mefloquine’s short- and long-term safety combined with availability of newer prophylactic drugs that were reported to have fewer side effects likely contributed to a decline in the number of mefloquine prescriptions (Leggat, 2005; Leggat and Speare, 2003). Mefloquine continues to be available and recommended by national and global agencies for the prophylaxis of malaria in chloroquine-resistant areas because it is effective against all Plasmodium species (Schlagenhauf et al., 2019). Despite the cautions of adverse effects, the once-per- week mefloquine regimen has been preferred by some groups (Senn et al., 2007). This chapter begins with a discussion of the changes that have been made to the mefloquine package insert since its approval in the United States in 1989, with par- ticular emphasis on information in the Contraindications, Warnings, and Pre­ autions c sections. This is followed by summaries of findings and conclusions regarding the use of mefloquine in military forces reported by U.S. agencies and foreign govern- ments. The known pharmacokinetics of mefloquine are then described, followed by a summary of the known short-term adverse events associated with use of ­ efloquine m when used as directed for prophylaxis. Most of the chapter is dedicated to sum- marizing and assessing the 11 identified epidemiologic studies that contributed some information on persistent or latent health outcomes following the cessation of mefloquine. These are arranged by the type of population that was examined: first, studies of military and veterans (U.S. followed by international forces), then occupational groups (U.S. Peace Corps), travelers, and, finally, research volunteers. Where available, studies of U.S. participants are presented first. A table that gives a high-level comparison of each of the 11 epidemiologic studies that examined the use of mefloquine and that met the committee’s inclusion criteria is presented in Appen- dix C. Supplemental supporting evidence is then presented, including other identi- fied studies of health outcomes in populations that used mefloquine for prophylaxis but that did not meet the committee’s inclusion criteria; case reports of persistent adverse events associated with mefloquine use; and information on adverse events associated with mefloquine use in selected subpopulations, such as women, women who are pregnant, people with low body mass index (BMI), those who have chronic health conditions, and those who concurrently use alcohol, marijuana, or illicit substances. After presenting the primary and supplemental evidence in humans, sup- porting literature from experimental animal and in vitro studies is then summarized. The chapter ends with a synthesis of the evidence presented and the inferences and conclusions the committee made from the available evidence. FOOD AND DRUG ADMINISTRATION PACKAGE INSERT FOR MEFLOQUINE This section describes selected information that can be found on the FDA label or in the package insert for mefloquine. It begins with a summary of contraindica-

MEFLOQUINE 93 tions for its use based on the most recent FDA label and package insert. This is followed by a brief synopsis of drug interactions that are known or presumed to occur with concurrent mefloquine use. The final subsection provides a chronologic overview of changes to the label or package insert from its U.S. approval in 1989 to the most recent label, updated in 2016. The presented changes are specific to mefloquine when used for prophylaxis (not treatment) and in adults (not infants or children). The dates of the labels are based on the dates that appeared in the labels themselves (documents downloaded from ­ rugs@FDA Search or National D Institutes of Health DailyMed websites) or, when no date appeared in the label, the action date listed on the website. Contraindications Mefloquine use is contraindicated in persons with a known hypersensitivity to mefloquine or related compounds (e.g., quinine and quinidine) and to drug- formulation excipients (FDA, 2016). It is also contraindicated for people with current depression, a recent history of depression, generalized anxiety disorder, psychosis, schizophrenia or other major psychiatric disorders, or with a history of convulsions (FDA, 2016). Although policies are in place to prevent those with a contraindication from being prescribed mefloquine, in practice it still happens. For example, accord- ing to an analysis using the UK-based Clinical Practice Research Datalink, from January 2001 through June 2012, 165,218 people had a recorded prescription for an antimalarial for prophylaxis, of whom 25,294 (15.3%) were prescribed mefloquine. People with contraindications to mefloquine were twice as likely to be prescribed a different antimalarial drug, but occasionally people with contra- indications were prescribed mefloquine (Bloechliger et al., 2014). However, no additional follow-up or analyses of any reported adverse events were conducted to determine whether those with contraindications were at higher risk or experienced more severe adverse events. Drug Interactions The Warnings section of the package insert alerts against using halofantrine or ketoconazole concomitantly or within 15 weeks of the last dose of mefloquine due to risk of sudden cardiac death that can result from prolongation of the QTc interval (FDA, 2016). Co-administration of other drugs that affect cardiac conduc- tion (e.g., anti-arrhythmic or beta-adrenergic blocking agents, calcium channel blockers, antihistamines or H1-blocking agents, tricyclic antidepressants, and p ­ henothiazines) might also contribute to a prolongation of the QTc interval (FDA, 2016). Administration of mefloquine with related antimalarials (e.g., quinine, quinidine, chloroquine) may produce electrocardiographic abnormalities and increase the risk of convulsions (FDA, 2016).

94 LONG-TERM HEALTH EFFECTS OF ANTIMALARIAL DRUGS Taking mefloquine with an anticonvulsant (e.g., valproic acid, ­ arbamazepine, c phenobarbital, or phenytoin) may reduce seizure control, and the blood level of anti-seizure medication should be monitored. Moreover, concomitant administra- tion of mefloquine with quinine or chloroquine in addition to an anti­ onvulsant c can further increase the risk of seizures. Taking mefloquine concurrently with oral live typhoid vaccines may make the immunization ineffective. It is recommended that vaccination with live attenuated bacteria be completed at least 3 days before beginning mefloquine. Taking rifampin with mefloquine can decrease mefloquine concentration and elimination time. Mefloquine is metabolized by CYP3A4, and CYP3A4 inhibitors may modify the pharmacokinetics and metabolism of m ­ efloquine and thus increase mefloquine plasma concentrations and the risk of adverse reactions. Similarly, CYP3A4 inducers may decrease mefloquine plasma concentrations and reduce mefloquine efficacy. Mefloquine is a substrate and an inhibitor of P-glycoprotein; thus drug–drug interactions could occur with drugs that are substrates or are known to modify the expression of this transporter, although the clinical relevance of these interactions is not known to date. Changes to the Mefloquine Package Insert Over Time There have been multiple important changes to the mefloquine package insert since the drug was first approved for prophylaxis and treatment of malaria in 1989. According to the FDA Center for Drug Evaluation and Research, for a drug to be approved by FDA, at a minimum it must be shown through submitted clinical trials, animal toxicology studies, and other evidence that the drug works as intended and that the health benefits outweigh the known risks (FDA, 2019a). Label changes may indicate that FDA has recognized potential problems with a drug but there may be other reasons for label changes, including approval for a new indication and expansion of the population for which the initial approval was obtained. Most safety-related label changes are the result of spontaneous adverse event reports that have been received during the postmarketing surveillance period, rather than well-designed epidemiologic studies, although if such epidemiologic studies are available they are considered along with new results from pharmacokinetic studies (Sekine et al., 2016). Moreover, the adverse event reports describe events that follow the reported use of the drug, and causality has not necessarily been proven. Many of the labeling-update letters and package inserts for mefloquine listed on the Drugs@FDA Search website for the period 1989–2002 were unavailable for download. (The downloadable package insert listed with a May 1989 action date is actually a July 2002 revision.) In response to a request for the unavailable information, FDA provided a PDF of the original 1989 package insert as well as abbreviated extractions from editions of the Physicians’ Desk Reference but noted

MEFLOQUINE 95 that the committee might want to confirm the summary information.1 In response to the committee’s request for the specific information upon which FDA based mefloquine-labeling changes, FDA stated that it had performed “safety ­ nalyses” a in 2007, 2013, 2015, and 2016 that supported labeling changes and that the committee could request redacted versions of these reviews via the Freedom of Information Act.2 In response to the committee’s request for the information that underlay the addition of the boxed warning to the mefloquine label, FDA referred the committee to the 2013 drug safety communication, a public announcement regarding the boxed warning (FDA, 2013a). The committee had quoted this docu- ment in its request to FDA, explaining that it sought more detail than the ­ ocument d provided. The 2013 drug safety communication states: “In conducting its assess- ment of vestibular adverse reactions associated with mefloquine use, FDA reviewed adverse event reports from the FDA Adverse Event Reporting System and the published literature, identifying patients that reported one or more vestibu- lar symptoms such as dizziness, loss of balance, tinnitus, and vertigo.” It notes fur- ther that “Patients who experienced vestibular symptoms usually had concomitant psychiatric symptoms such as anxiety, confusion, paranoia, and depression. Some of the psychiatric symptoms persisted for months to years after mefloquine was discontinued.” As desired details were not provided about the evidence base for the labeling changes (e.g., quantification of adverse reactions reported, epidemiologic data), it was difficult for the committee to assess the implications of the changes. A comparison of the 1989 package insert and the 2002 package inserts (July and December) showed numerous additions, many pertaining to neurologic and psychiatric adverse events, which were often grouped as “neuropsychiatric” (see Table 4-1 for a summary of the major changes to the package insert over time regarding neuropsychiatric adverse events). The 1989 version stated that “neuropsychiatric reactions have been reported during the use of Lariam” and warned that “if signs of unexplained anxiety, depression, restlessness or confu- sion are noticed, these may be considered prodromal to a more serious event” and the drug must be discontinued (FDA, 1989). The 2002 package insert added information on neuropsychiatric symptoms to the Contraindications and Warnings sections (FDA, 2002). Mefloquine used as prophylaxis was now contraindicated in persons with current psychiatric problems or a history of psychiatric disorders or convulsions. Symptoms that in 1989 had been listed in the Adverse Reactions’ postmarketing surveillance section as “additional adverse reactions”—vertigo, visual disturbances, and central nervous system disturbances (e.g., psychotic mani- festations, hallucinations, confusion, anxiety, and depression)—now appeared in 1  Personal communication to the committee, Kelly Cao, Pharm.D., Safety Evaluator Team Leader, Division of Pharmacovigilance II, Office of Pharmacovigilance and Epidemiology, Office of Surveil- lance and Epidemiology, Center for Drug Evaluation and Research, March 20, 2019. 2  Personal communication to the committee, Division of Drug Information, Center for Drug Evalu- ation and Research, FDA, April 30, 2019.

96 LONG-TERM HEALTH EFFECTS OF ANTIMALARIAL DRUGS TABLE 4-1 Evolution of Neuropsychiatric Safety-Related Information in the FDA Mefloquine Package Insert and Medication Guide Issue Date Action 1989 FDA approval of Lariam; first package insert 2002 Additions to the Contraindications, Warnings, Precautions, and Adverse Reactions sections of package insert 2003 FDA requires Medication Guide be given to persons to whom drug is dispensed 2008 Additions to the Precautions section of package insert Additions to Medication Guide 2009 FDA requires manufacturer to submit a risk evaluation and mitigation strategya 2011 Risk evaluation and mitigation strategy is no longer required 2013 Boxed warning (“black box”), the most serious kind of warning about potential problems, added to package insert Additions to Warnings and Animal Toxicology sections of package insert Additions to Medication Guide 2016 No substantive changes to package insert a A risk evaluation and mitigation strategy (REMS) is a drug safety program that FDA requires for certain medications with serious safety concerns. They are designed to help reduce the occur- rence and/or severity of certain serious risks and to ensure the benefits of the medication outweigh

MEFLOQUINE 97 Summary of Relevant Content in Package Insert, Medication Guide, or FDA Letters to Manufacturer • Neuropsychiatric reactions have been reported • Discontinue use if unexplained anxiety, depression, restlessness or confusion occur as it may be considered prodromal to a more serious event • Exercise caution when driving, piloting airplanes, or operating machinery • Contraindications added for those with current or past history of psychiatric disorders or convulsions and for those with hypersensitivity to mefloquine • Symptoms previously listed in Adverse Reactions (postmarketing surveillance) are moved to Warnings section, with additional symptoms, including thoughts of suicide • Text added that psychiatric symptoms may continue long after mefloquine use ceases • Precautions expanded regarding performing activities requiring alertness and fine motor coordination • Numerous symptoms are added to Adverse Reactions (postmarketing surveillance) section • Lists contraindications and possible neuropsychiatric side effects, including thoughts of suicide • Notes side effects may continue after drug is stopped • Cautions to exercise care driving and performing activities requiring alertness and fine motor coordination • Advised to consult health care provider if sudden onset of anxiety, depression, restlessness, or confusion occurs • Vertigo added as side effect (package insert and medication guide) • Dizziness or vertigo and loss of balance have been reported to continue for months after discontinuation of the drug (package insert and medication guide) • Feeling restless added as side effect (medication guide) • Assessment of REMS that should include an evaluation of: – Patients’ understanding of the serious risks of mefloquine – A report on periodic assessments of the distribution and dispensing of the medication guide in accordance with 21 CFR 208.24 – A report on failures to adhere to distribution and dispensing requirements, and corrective actions taken to address noncompliance • “The Medication Guide will continue to be part of the approved labeling.” • Boxed warning: “Mefloquine may cause neuropsychiatric adverse reactions that can persist after mefloquine has been discontinued. Mefloquine should not be prescribed for prophylaxis in patients with major psychiatric disorders. During prophylactic use, if psychiatric or neurologic symptoms occur, the drug should be discontinued and an alternative medication should be substituted.” • Neurologic symptoms such as dizziness or vertigo, tinnitus, and loss of balance may occur early in the course of mefloquine use and have been reported to continue for months or years after mefloquine has been stopped • Dizziness or vertigo, tinnitus, and loss of balance have been reported to be permanent in some cases • If the drug is to be administered for a prolonged period, periodic evaluations for neuropsychiatric effects should be performed • Animal studies demonstrated that mefloquine daily for 22 days at equivalent human therapeutic concentration showed central nervous system penetration of mefloquine, with a 30- to 50-fold greater brain/plasma drug ratio up to 10 days after final dose its risks. While all medications have labeling that provides information about medication risks, few medications require a REMS (FDA, 2019b).

98 LONG-TERM HEALTH EFFECTS OF ANTIMALARIAL DRUGS the ­ arnings section. The Warnings section also stated that psychiatric symptoms W “ranging from anxiety, paranoia, and depression to hallucinations and psychotic behavior” had been “reported to continue long after mefloquine has been stopped” (FDA, 1989, 2002). In addition, it noted, “Rare cases of suicidal ideation and sui- cide have been reported” (FDA, 2002). Cautions were expanded for mefloquine use while performing certain activities, specifically actions requiring alertness and fine motor coordination, “as dizziness, a loss of balance, or other disorders of the central or peripheral nervous system have been reported during and fol- lowing the use of Lariam” (FDA, 2002). The Adverse Reactions’ postmarketing surveillance section listed as among the most frequently reported adverse events dizziness or vertigo, loss of balance, and neuropsychiatric events such as headache, somnolence, and sleep disorders (insomnia, abnormal dreams) (FDA, 2002). This section also added a lengthy list of “more severe neuropsychiatric disorders” that had “occasionally” been reported (FDA, 2002). The Precautions section now warned, “Hypersensitivity reactions ranging from mild cutaneous events to anaphylaxis cannot be predicted” (FDA, 2002). Users were also advised that contraception should be practiced for up to 3 months after drug cessation and that mefloquine use should be weighed carefully in patients aged ≥65 years since electrocardiographic abnormalities had been observed and cardiac disease is more prevalent in older patients (FDA, 2002). Updates to information about other body systems included alerts that the con- comitant administration of mefloquine and quinine or chloroquine may increase the risk of convulsions. Taking halofantrine after mefloquine might cause potentially fatal prolongation of the QTc interval on electrocardiograms (ECGs); theoretically, the co-administration of other drugs affecting cardiac conduction might also have that effect (FDA, 2002). Previously, users had been informed that if the drug was administered for a prolonged period, periodic evaluations, including liver function tests, should be performed; this language was strengthened to note that in those with impaired liver function, elimination of mefloquine may be prolonged, lead- ing to higher plasma levels (FDA, 2002). The postmarketing surveillance section listed among “infrequent adverse events” cardiovascular, skin, and musculoskeletal disorders as well as “visual disturbances, vestibular disorders including tinnitus and hearing impairment, dyspnea, asthenia, malaise, fatigue, fever, sweating, chills, dyspepsia and loss of appetite.” The two serious adverse reactions reported were cardiopulmonary arrest in one patient shortly after ingesting a single ­ rophylactic p dose of mefloquine while using propranolol and, second, encephalopathy of unknown etiology during prophylactic mefloquine administration. In 2003 FDA required that pharmacists provide a medication guide—a paper handout that conveys risk information that is specific to a particular drug or drug class—to persons to whom mefloquine was dispensed (FDA, 2003a,b). The medi- cation guide included labeled cautions and contraindications and advised users to consult a health care provider in the case of a sudden onset of anxiety, depression, restlessness, or confusion (FDA, 2003b). In 2008 the package insert’s ­ recautions P

MEFLOQUINE 99 section added vertigo as a side effect and stated that “in a small number of patients, dizziness and loss of balance have been reported to continue for months after mefloquine has been stopped” (FDA, 2008). The medication guide warned users that they might suddenly experience severe anxiety, paranoia, hallucinations, depression, unusual behavior, and disorientation; “feeling restless” was added to possible side effects. The Adverse Reactions postmarketing surveillance section added respiratory disorders to “infrequent adverse events.” In the 2009 package insert, the Warnings section alerted users against co-administration of halofantrine or ketoconazole with mefloquine; several additions were also made to the Drug Interactions section (FDA, 2009). In 2013 FDA strengthened and updated warnings of previously included neurologic and psychiatric side effects, and it added a boxed warning, sometimes ­ informally referred to as a “black box” (FDA, 2013b). This is FDA’s most serious type of warning, and it appears on a prescription drug’s label to call attention to seri- ous or life-threatening risks (FDA, 2012). The boxed warning stated, “Mefloquine may cause neuropsychiatric adverse reactions that can persist after mefloquine has been discontinued,” and it added that mefloquine should not be prescribed in patients with major psychiatric disorders and that if psychiatric or neurologic symp- toms occur during prophylactic use, drug use should be halted (FDA, 2013b). The W ­ arnings section now informed users that psychiatric symptoms “may occur early in the course of mefloquine use and that in some cases, symptoms have been reported to continue for months or years after mefloquine has been stopped” (FDA, 2013b). It also warned that neurologic effects, including dizziness, vertigo, loss of balance, and ringing in the ears, could occur soon after starting the drug and that they could per- sist or become permanent. It recommended that evaluations for “neuro­ sychiatric” p effects be performed in persons using the drug long term. Prior language that stated that no relationship had been established between mefloquine and suicide or suicidal thoughts was deleted. Users with impaired liver function were now warned that this placed them at a higher risk of adverse reactions. The Toxicology section included a study in which rats given mefloquine daily for 22 days at levels equivalent to human therapeutic levels showed that mefloquine penetrated the central nervous system, with a 30- to 50-fold greater brain/plasma drug ratio up to 10 days after drug cessa- tion. In the Adverse Reactions postmarketing surveillance section, hepatobiliary dis- orders, and blood and lymphatic system disorders were added to the “less frequently reported adverse reactions.” The most recent update to the package insert was made in 2016, and added ocular effects to the Warnings section (FDA, 2016). Regarding adverse events, the package insert states that the most frequently observed adverse event in clini- cal trials of malaria prophylaxis was vomiting (3%). Dizziness, syncope, extra­ systoles, and other complaints were reported in less than 1% of users. Postmarket- ing surveillance has found that the most frequently reported adverse events are nausea, vomiting, loose stools or diarrhea, abdominal pain, dizziness or ­ ertigo, v loss of balance, and “neuropsychiatric” events such as headache, ­ omnolence, s

100 LONG-TERM HEALTH EFFECTS OF ANTIMALARIAL DRUGS and sleep disorders (insomnia, abnormal dreams). These adverse events are often reported without reference to a comparison group, and their duration is rarely detailed. The Warnings section of the package insert includes several adverse events. It warns that psychiatric symptoms such as acute anxiety, depression, restlessness, or confusion should be viewed as potential precursors to more serious psychiatric or neurologic adverse reactions and that when they occur, mefloquine should be discontinued. More severe neurologic and psychiatric disorders have been reported, including sensory and motor neuropathies (including paresthesia, tremor, and ataxia), convulsions, agitation or restlessness, anxiety, depression, mood swings, panic attacks, memory impairment, confusion, hallucinations, aggres- sion, psychotic or paranoid reactions, and encephalopathy. Suicidal thoughts and suicide have been also been reported. Neurologic symptoms including dizziness or vertigo, tinnitus, hearing loss, and loss of balance have been reported to occur after beginning the drug regimen and in some cases have continued for months, years, or even permanently after discontinuing mefloquine. Users are instructed to discontinue the drug if neurologic symptoms occur, and to use caution when performing activities requiring alertness and fine motor coordination (e.g., driving, piloting aircraft, operating machinery, and deep-sea diving) (FDA, 2016). Other short-term adverse events reported with the use of mefloquine have included transitory and clinically silent ECG alterations such as sinus bradycardia, sinus arrhythmia, first degree atrial–ventricular (AV) block, prolongation of the QTc interval, and abnormal T waves. Eye disorders, including optic neuropathy and retinal disorders, have also been reported during mefloquine use. POLICIES AND INQUIRIES RELATED TO THE USE OF MEFLOQUINE BY MILITARY FORCES This section reviews some of the policies regarding the use of mefloquine in U.S. and foreign militaries. When identified, the committee also considered issued reports by other countries (Australia, Canada, and the United Kingdom) on the use of mefloquine in their militaries, although this list is not meant to be exhaustive. United States Mefloquine was possibly used by the U.S. military as early as 19903 and by other military forces as early as 1986 (Croft and Geary, 2001). It was used as a first-line prophylactic agent only for deployments to high-malaria-risk areas in sub-Saharan Africa, such as for the Liberian Task Force in 2003, and it was 3  Personal communication to the committee, COL Andrew Wiesen, M.D., M.P.H., Director, Preven- tive Medicine, Health Readiness Policy, and Oversight, Office of the Assistant Secretary of Defense (Health Affairs), DoD, April 16, 2019.

MEFLOQUINE 101 used as a second-line agent in Operation Enduring Freedom (OEF; 2001–2014), Operation Iraqi Freedom (OIF; 2003–2010), and Operation New Dawn (OND; 2010–2011). In 2003 a Department of Defense (DoD) memorandum on antimalarials was issued by the Armed Forces Epidemiological Board (DoD, 2003). The authors note first that DoD is subject to Section 1107 of Title 10, United States Code, regard- ing the off-label use of force health protection medications. It then states that this would limit the prescription of Centers for Disease Control and Prevention (CDC)- recommended off-label prophylactic regimens (e.g., a loading dose of mefloquine for persons being deployed on short notice) to the context of a doctor–patient relationship or an investigational new-drug protocol, both of which could be prob- lematic in a military setting. In its findings and recommendations, the board stated that it found the CDC consensus guidelines for malaria prevention “appropriate” for use by DoD and listed three options (A/P, mefloquine, and doxycycline) for areas with chloroquine-resistant P. falciparum. It noted that the contraindications for mefloquine were active depression and a history of psychosis or seizures and that it should be used cautiously in those with psychiatric disturbances. The board stated that mefloquine should continue to be available in the military drug arma- mentarium for malaria prophylaxis. The committee reviewed a June 2004 “health information letter” that the U.S. Veterans Health Administration issued to clinicians caring for veterans who may have taken mefloquine as prophylaxis during OEF or OIF (VA, 2004). The Department of Veterans Affairs (VA) noted that mefloquine causes adverse events, possibly affecting adherence, and that anecdotal and media reports had suggested that the drug may cause serious neuropsychiatric effects. The letter also cited a DoD mefloquine “warning label” for clinicians that stated mefloquine should not be prescribed to persons “with a history of psychiatric or alcohol problems.” The VA letter described a literature review that had been performed and noted that the literature (based on case reports, clinical trials, and epidemiologic studies with no separation of the timing of adverse events) suggested that “certain health effects of mefloquine may persist after the drug is stopped.” It also stated that “clinical ­rials t and epidemiological studies suggest that reported side effects are not common and are self-limiting” and that they included depression, panic attacks, anxiety, insomnia, vertigo, nausea and headache, and strange or vivid dreams. VA told the committee that such health information letters were used to provide information to VA staff and are not policy and that no record of additional information letters on the subject of mefloquine had been found.4 The VA letter listed all of the published sources that were used in drawing its conclusions. The committee considered all of those case reports and studies captured by VA for its own assessment but found 4  Personal communication to the committee, Peter D. Rumm, M.D., M.P.H., F.A.C.P.M., Director, Pre-9/11 Era Environmental Health Program, VA, June 6, 2019.

102 LONG-TERM HEALTH EFFECTS OF ANTIMALARIAL DRUGS that most did not meet its criteria of reporting empirical data on adverse events that persist or occur at least 28 days post-cessation of mefloquine. In response to the committee’s request for further information on the DoD “warning label,” VA could not provide it, and DoD responded that it does not issue warning labels.5 DoD provided copies of information sheets for service members and their families (dated 2004) and for leaders (dated 2005) that had been available on the health.mil website (DoD, 2004, 2005a). These guides, in addition to warning against mefloquine use in those with a current or past history of psychiatric disorders, repeatedly warned against drinking alcohol while taking the drug because “alcohol may interfere with the medicine’s effectiveness and cause more serious side effects.” FDA mefloquine package inserts, including the most recent 2016 version, do not provide warnings or guidance on concurrent alcohol use (FDA, 2016). In 2005 a DoD issuance outlined the U.S. Central Command deployment health protection policy (DoD, 2005b). It noted that component Combined Joint Task Force surgeons were authorized to modify malaria prophylaxis guidance for subordinate units based on latest intelligence, ground truth, and medical-risk assessment. The issuance stated that a mefloquine or doxycycline regimen must be used by personnel deploying to Central Asia, the Arabian Peninsula, and Africa; it stated further that mefloquine was not authorized for people on flight status. A 2006 DoD policy memorandum directed that mefloquine be used by Coalition Forces Land Component Command personnel traveling to the Combined Joint Task Force–Horn of Africa area of operations; it instructed aviators and individuals unable to take mefloquine to take doxycycline (DoD, 2006). The National Defense Authorization Act for Fiscal Year 2006 required the Secretary of Defense to conduct a study of adverse health events (including mental health) that may be associated with the use of antimalarial drugs, including mefloquine.6 In response, the assistant secretary of defense for health affairs commissioned four scientific studies to assess the comparative rates of adverse events resulting from the use of antimalarial medications, including mefloquine, chloroquine, doxycycline, and A/P, in deployed service members (DoD, 2009a). One study associated with this charge was published (Wells et al., 2006), and it is summarized in the Post-Cessation Adverse Events section of this chapter. Another study was reported to have been completed but not published. This committee has no information on other studies that may have been commissioned in association with this charge. 5  Personal communication to the committee, COL Andrew Wiesen, M.D., M.P.H., Director, Preven- tive Medicine, Health Readiness Policy, and Oversight, Office of the Assistant Secretary of Defense (Health Affairs), DoD, June 10, 2019. 6  National Defense Authorization Act, Public Law 109-360, report on adverse health events associ- ated with use of anti-malarial drugs, § 737, December 18, 2005.

MEFLOQUINE 103 In 2009 a DoD memorandum advised that in chloroquine-resistant areas where doxycycline and mefloquine are equally efficacious and when personnel have a history of neurobehavioral disorders, doxycycline should be the first-line agent, A/P should be the second-line agent, and, in those who cannot take doxycycline or A/P, mefloquine should be used very cautiously and with clinical follow-up (DoD, 2009b). The memo also stated, presumably regarding personnel with no history of neurobehavioral disorders, that mefloquine should only be used by those with contraindications to doxycycline and without contraindications to mefloquine. In a retrospective analysis of 11,725 active-duty U.S. military personnel who were assigned in support of combat and reconstruction operations in Afghanistan around 2007, DoD administrative databases were used to determine the number of personnel with medical or pharmacologic contraindications to mefloquine prior to their deployment (Nevin, 2010; Nevin et al., 2008). In this cohort, 4,505 (38.4%) service members received a prescription for mefloquine, including 155 (13.7%) of the 1,127 service members with an identified medical or pharmacologic contra­ indication to mefloquine. A 2013 DoD memo stated that doxycycline and A/P were to be considered first-line agents in chloroquine-resistant areas, reserving meflo- quine for use by those intolerant to or with contraindications to both doxycycline and A/P (DoD, 2013a). The same year, a DoD issuance stated that U.S. Special Operations Command medical personnel were to immediately cease prescribing and using mefloquine for prophylaxis and that personnel currently taking meflo- quine were to transition to one of three alternative medications (DoD, 2013b). Total DoD mefloquine prescriptions fell from 23,889 in 2008 (18,942 active duty) to 263 (52 active duty) in 2017, representing a 99% reduction (99.8% among active duty) (Wiesen, 2019). Australia Although mefloquine continues to be recommended by WHO and CDC for malaria prophylaxis in civilians, several militaries have issued policies regarding its use in their members. Since 2015 the governments of Australia, Canada, and the United Kingdom have performed inquiries or investigations into the pos- sible association of mefloquine with adverse effects, particularly neurologic and psychiatric effects, when used for malaria prophylaxis by their military forces (Australia, 2018; Canada, 2017; UK, 2016). Both the Canadian and Australian governments performed a literature review as a part of their inquiry process (Aus- tralia, 2018; Canada, 2017). Concerns raised by veterans and commentary in the media contributed to the initiation of these inquiries. Military veterans of Canada, Ireland, and the United Kingdom have filed lawsuits against their governments, holding them responsible for adverse events they state were caused by mefloquine use during their military service, and a U.S. veteran has filed a lawsuit against Hoffman-La Roche, the manufacturer of Lariam® (BBC, 2016; Connolly, 2019; O’Faolain, 2019).

104 LONG-TERM HEALTH EFFECTS OF ANTIMALARIAL DRUGS As part of its inquiry, the Australian Senate commissioned a literature review of mefloquine and a research study that involved a re-analysis of health study data on antimalarial use from the 2007–2008 Centre for Military and Veterans’ Health deployment health studies (Australia, 2018). It heard or reviewed submit- ted testimony from government agencies (Department of Defence, Department of Health, Department of Veterans’ Affairs, Australian Defence Force Malaria and Infectious Disease Institute, Indo-Pacific Centre for Health Security, Department of Foreign Affairs and Trade Repatriation Medical Authority), a malaria-control organization (Asia Pacific Leaders Malaria Alliance), professional medical asso- ciations (­ ustralasian Society for Infectious Diseases, Australasian College of A Tropical Medicine, Royal Australian College of General Practitioners), advocate organizations (Australian Quinoline Veterans and Families Association, Quinism Foundation, Defence Force Welfare Association, Royal Australian Regiment C ­ orporation, RSL National), and product-development partnerships and phar- maceutical manufacturers (Medicines for Malaria Venture, National Health and Medical Research Council, GlaxoSmithKline, Biocelect, 60 Degrees Pharmaceu- ticals, Roche), as well as from roughly 25 individuals, including­ hysicians, aca- p demics, and veterans. In submitted testimony, symptoms attributed to mefloquine use were referred to as “mefloquine poisoning” or an “acquired brain injury” by the Australian Quinoline Veterans and Families Association and as “chronic q ­ uinoline encephalopathy” or “neuropsychiatric quinism” by the U.S.-based Quinism Foundation (Australia, 2018). Some veterans attributed their symptoms to mefloquine use 15 or more years earlier. In the report summary, while the Australian Senate committee acknowledged that its members were not medical experts, it stated, “The weight of prevailing medical evidence provided to the committee in response to these claims is that long term problems as a result of tak- ing mefloquine are rare,” and it added that the committee had been informed that there was no definitive evidence to support the claim that mefloquine use results in acquired brain injury. It stated that while it believed that symptoms were being experienced by individuals, assigning a single cause to these illnesses did not take into account the multiple potential contributors to their health while they took the drug and in the years after. The committee recommended that the ­ ustralian A Department of Veterans’ Affairs expedite its investigation into anti­ alarial m claims logged since September 2016 and that it offer assistance to claimants and facilitate their access to legal representation. That committee also made recom- mendations to ensure better access to care for sick veterans, including that the Australian Department of Veterans’ Affairs prioritize developing a neurocognitive health program. It did not recommend that changes be made to military policy on antimalarial use, which currently allows mefloquine to be prescribed as a “third line agent” only when doxycycline or A/P are contraindicated. Few Australian Defence Force members have been prescribed mefloquine since 2010; in 2017 only two prescriptions were made (Australian Department of Defence, n.d.).

MEFLOQUINE 105 Canada The Canadian Armed Forces recommends the use of A/P, doxycycline, and mefloquine for malaria prophylaxis in addition to other measures to prevent mosquito bites. The Canadian Armed Forces follows the guidance set forth by the Public Health Agency of Canada. Individual armed forces members, in consultation with their health care providers, make a personal and informed decision on which antimalarial drug they want to be prescribed (Canada, 2017). Similar to the U.S. and Australian military experiences, the number of mefloquine prescriptions has decreased since 2010; 20 prescriptions were made in 2016 (Canadian Forces Health Services Group, 2017). The Canadian Surgeon General report, which was developed by a task force of Canadian Armed Forces personnel and civilians from the Department of National Defence, examined the Canadian Armed Forces experience with mefloquine and conducted a systematic review and assessment of military-specific safety information compared with other available antimalarial drugs (Canada, 2017). Although the report concluded that mefloquine was not associated with an overall excess risk of adverse effects in force personnel and its use did not prevent personnel from being able to perform their occupational duties, the quality of the evidence of the available published literature on the long-term health effects of mefloquine compared with other available antimalarial drugs was weak and itself did not support a change to policy. However, based on a consideration of other factors, such as most members showing a preference for the other available agents (A/P and doxycycline), the fact that screening for potential contraindications was lacking (a medical chart audit showed that 12% of mefloquine prescriptions had been made to service members who had contraindications), the lack of evidence on long-term safety, a desire for consistency with allied militaries (such as the United States), and the desire to be responsive to defence force member and societal concerns, the report recommended that the military change its policy to limit mefloquine use to (1) persons for whom use of A/P, doxycycline, and chloroquine are inappropriate (e.g., due to contraindications or intolerance); and (2) persons who have previously used and tolerated mefloquine, indicate a preference for it, and do not have contraindications. The report further recommended that the Canadian Armed Forces develop policies or procedures to enhance screening (and screening documentation) of service members for contraindications to mefloquine and other antimalarials and that a formal audit process be implemented to enable monitoring of antimalarial screening and prescription practices (Canada, 2017). United Kingdom The UK Ministry of Defence amended its policy regarding the use of meflo- quine and other antimalarials on September 12, 2016, and it was further revised in June 2017 in response to recommendations from the UK House of Commons

106 LONG-TERM HEALTH EFFECTS OF ANTIMALARIAL DRUGS Defence Committee’s report on mefloquine (UK, 2016). The inquiry by the House of Commons Defence Committee was more limited in scope than those undertaken by the Australian and Canadian governments. The committee did not perform a literature search, but testimony was heard and reviewed from government agencies (Surgeon General; Ministry for Defence Personnel, Welfare and Veterans; Defence Medical Services), the pharmaceutical manufacturer Roche Products Ltd., and roughly 15 individuals, including a research scientist, physicians, and veterans. That committee concluded that mefloquine should be considered as a drug of last resort in defense forces. The new policy restricts the use of mefloquine even more narrowly to military personnel who are unable to tolerate available alternatives, have been screened for safe use via a face-to-face assessment, and have been informed of and provided the option to take alternative agents. The other prophy- lactic drugs available to armed forces members are doxycycline, chloroquine, and A/P. Consistent with Australian and Canadian defense forces, few prescriptions for mefloquine are made; from April 2018 to March 2019, there were 31 mefloquine prescriptions (UK, 2019). PHARMACOKINETICS Mefloquine is a chiral antimalarial agent, available as the racemic combina- tion of (+) and (–) enantiomers (Schlagenhauf, 1999). Five metabolites of meflo- quine have been isolated (WHO, 1983). The pharmacokinetics of the mefloquine enantiomers have been found to be highly stereospecific (Gimenez et al., 1994). The plasma concentrations of the (–) enantiomer were shown to be significantly higher than those observed for the (+) enantiomer, and all major pharmacokinetic parameters, with the exception of Tmax, were observed to be significantly different (Gimenez et al., 1994). Mefloquine is primarily metabolized by CYP3A4 (Fontaine et al., 2000), and the major circulating metabolite is a 4-carboxyclic acid derivative (Gimenez et al., 1994), which is inactive against P. falciparum (Ashley et al., 2006). Mefloquine appears to be excreted primarily in the bile and feces; urine excretion of the unchanged drug and of its acid metabolite amounted to 9% and 4.2% of the weekly dose, respectively (Schwartz et al., 1987; WHO, 1983). Plasma protein binding of mefloquine is high, reportedly 98% (Karbwang and White, 1990; Palmer et al., 1993). Considerable interindividual variation in pharmacokinetic parameters has been reported (Gimenez et al., 1994; Karbwang and White, 1990; Karbwang et al., 1987; Palmer et al., 1993). The presence of food significantly increases the bioavailability of mefloquine (Schlagenhauf, 1999). In healthy volunteers, plasma concentrations peak 6–24 hours (mean 17.6 hours) after a single dose of mefloquine (Palmer et al., 1993). Clinical pharmacokinetic studies in male volunteers from Africa, Brazil, Europe, and the United States have shown that mefloquine has a long but variable plasma half-life of 6–23 days, with a mean

MEFLOQUINE 107 value of around 14 days, but effective drug levels may persist for 30 days or more (WHO, 1983). Using a dosage of 250 mg weekly requires 7–10 weeks before a steady-state plasma concentration is achieved. Maximum blood concentrations appear to be two to three times higher in Asians than in non-Asians. In healthy adults, the terminal elimination half-life ranges from 14 to 28 (mean 18.1) days, indicating that mefloquine is distributed extensively in the tissues and is cleared slowly from the body (Palmer et al., 1993). Mefloquine blood concentrations in pregnant women are lower than those in nonpregnant adults (Thillainayagam and Ramaiah, 2016), but clearance may be increased during late pregnancy (Karbwang and White, 1990). ADVERSE EVENTS This section begins with a summary of known concurrent adverse events, such as those that occur immediately or within a few hours or days of taking a dose of mefloquine, from Cochrane systematic reviews. Epidemiologic studies of persistent adverse events in which information was available at least 28 days post- mefloquine-cessation are then summarized by population category (military or veterans, occupational groups, travelers, and research volunteers), with an empha- sis placed on reported results of persistent or latent effects that were associated with the use of mefloquine (even if results on other antimalarial-drug comparison groups were presented). Concurrent Adverse Events Concurrent adverse events are well characterized for mefloquine. In general, mefloquine has a poorer reputation among the public and in military populations than the other available drugs for malaria prophylaxis. This is due mainly to the neurologic and psychiatric events associated with mefloquine, which are dose related, but that may occur at prophylactic doses (Stürchler et al., 1990; Weinke et al., 1991) and at a greater frequency than with other antimalarial ­ rophylactics p (Schlagenhauf et al., 2003, 2010). However, mefloquine-associated serious adverse events—defined as those that constitute a threat to life, require hospital- ization, or result in severe disability—are rare, with estimated occurrences ranging from 1 in 10,000 to 1 in 20,000 depending on the population examined (­ jörkman B et al., 1991; Schlagenhauf et al., 2003, 2010; Stürchler et al., 1990; Weinke et al., 1991; Wells et al., 2006). Instead of detailing every study that has reported concurrent adverse events that have been reported with use of mefloquine, the fol- lowing paragraphs summarize the most common adverse events as well as those that are less commonly reported but still recognized as possibly related to the use of mefloquine for malaria prophylaxis using two identified Cochrane systematic reviews of the literature (Croft and Garner, 2000; Tickell-Painter et al., 2017a).

108 LONG-TERM HEALTH EFFECTS OF ANTIMALARIAL DRUGS Results from analyses that compared mefloquine with placebo or no drug (as opposed to comparisons with another antimalarial drug) were of greatest interest to the committee because an observed lack of difference in effect between two drugs could occur because both drugs cause the (same) adverse events. Use of a placebo-controlled design helps provide information about the “base rate” of the adverse events, to understand if the rates observed among individuals taking the drug are higher than would be expected with no drug exposure. The aim of the first published Cochrane review (Croft and Garner, 2000) was to determine the effects of mefloquine in nonimmune adult travelers compared with other antimalarial regimens in relation to episodes of malaria, withdrawal from prophylaxis, and adverse events. Ten randomized trials of adult travelers and non-traveling volunteers were considered as well as 516 case reports for adverse events analyses. More recently, Tickell-Painter et al. (2017a) conducted a systematic review to summarize the efficacy and safety of mefloquine used as ­ rophylaxis for malaria in adults, children, and pregnant women travelers. This p review included 20 randomized controlled trials (totaling 11,470 participants), 35 cohort studies (totaling 198,493 participants), and 4 large retrospective analyses of health records (800,652 participants). Although the aims of these two large reviews were slightly different, Tickell-Painter et al. included nearly all of the same randomized controlled trials as Croft and Garner. Croft and Garner (2000) assessed the use of mefloquine in nonimmune adult travelers compared with other regimens; the analysis included a total of 2,750 participants. To compare tolerability, the authors reviewed data on neurologic and psychiatric symptoms (depression, abnormal dreams, fatigue, headache, insomnia), gastrointestinal symptoms (abdominal discomfort, anorexia, diarrhea, nausea, vomiting), and fever and pruritus; data were to have been collected “at first assessment.” The authors identified five trials that compared outcomes with mefloquine versus placebo, and they reported that the tolerability outcome mea- sures showed no statistically significant pattern relative to mefloquine or placebo, but that the numbers of study participants were generally small. Six trials were identified that compared mefloquine with other malaria-prophylactic drugs, but the comparator drugs were not named, except incidentally when specific com- parisons were made. The authors calculated Peto odds ratios (used when pooling odds ratios) and found the overall incidence of adverse events with mefloquine to be no different from that of other antimalarials (OR = 1.00, 95%CI 0.80–1.27; 4 studies, 1,344 participants). There was no consistent pattern across the five neurologic and psychiatric symptoms analyzed (depression, dreams, fatigue, headache, insomnia), but mefloquine was shown to be more likely than other agents to cause insomnia (OR = 1.64, 95%CI 1.18–2.28; 4 studies, 1,344 partici- pants) and fatigue (OR = 1.57, 95%CI 1.01–2.45; 4 studies, 1,344 participants). No consistent pattern was seen for the gastrointestinal symptoms analyzed, but abdominal discomfort was reported less frequently among users of mefloquine than among users of other antimalarials (OR = 0.57, 95%CI 0.42–0.77; 5 studies,

MEFLOQUINE 109 1,464 participants), as was the case with anorexia (OR = 0.64, 95%CI 0.43–0.95; 4 studies, 1,444 participants) and nausea (OR = 0.74, 95%CI 0.57–0.96; 6 ­ tudies, s 1,717 participants). The authors noted the heterogeneity of the studies and stated that the overall effect regarding gastrointestinal symptoms appeared to be due to one study in which participants reported symptoms in the chloroquine-proguanil group more frequently than in the mefloquine group. Reports of fever and ­ ruritus p were similar in the mefloquine and comparator arms. The authors also noted that they had identified 328 case reports that involved mefloquine prophylaxis and adverse events (discussed later in this chapter under Case Reports and Case Series). Tickell-Painter et al. (2017a) prespecified adverse events of interest to include these disorders: psychiatric (abnormal dreams, insomnia, anxiety, depression, p ­ sychosis); nervous system (dizziness, headache); ear and labyrinth (vertigo); eye (visual impairment); gastrointestinal tract (nausea, vomiting, abdominal pain, diarrhea, dyspepsia); and skin and subcutaneous tissues (pruritus, photo­ ensitivity, s vaginal candida). The assessment comparing the use of mefloquine for malaria prophylaxis with placebo or no treatment included 13 randomized controlled trials and 5 cohort studies. Dosages varied, as did methods of collecting adverse event data; eight of the trials were considered to be at high risk of bias from selective outcome reporting. The authors applied categories of certainty to the results based on the five GRADE considerations (risk of bias, consistency of effect, imprecision, indirectness, and publication bias) (Higgins et al., 2019). Overall, among the six randomized controlled trials only one serious adverse event (death from septic shock after an emergency cesarean section for obstructed labor) was reported among study participants who used mefloquine (n = 592) compared with two that occurred among people using placebo (n = 629); none of these events were attributed to the drug regimen (Tickell-Painter et al., 2017a). In the cohort studies, seven serious adverse events (five were depression and two were dizziness, and all were attributed to the drug regimen) were reported among 913 mefloquine users, and none were reported in 254 ­ravelers who did t not use antimalarials. When analyses were performed to compare mefloquine with d ­ oxycycline (4 trials and 20 cohort studies), A/P (3 trials and 16 cohort studies), and chloroquine (6 trials and 15 cohort studies), no difference in the incidence of serious adverse events was found between mefloquine and doxycycline, A/P, or chloroquine. Participants receiving mefloquine were no more likely to discon- tinue their medication due to adverse events than were doxycycline users (RR = 1.08, 95%CI 0.41–2.87; 4 trials, 763 participants; low-certainty evidence), but mefloquine users were more likely to discontinue their medication due to adverse events than A/P users (RR = 2.86, 95%CI 1.53–5.31; 3 trials, 1,438 participants; high-certainty evidence) (Tickell-Painter et al., 2017a). Regarding neurologic outcomes, people taking mefloquine were less likely than those taking placebo in trials to experience headache (RR = 0.84, 95%CI 0.71–0.99; 5 trials, 791 participants), but this was not observed in the one cohort

110 LONG-TERM HEALTH EFFECTS OF ANTIMALARIAL DRUGS study that reported on headache. Whereas mefloquine users in trials were no more likely than recipients who took a placebo or no drug to experience dizziness (RR = 1.03, 95%CI 0.90–1.17; 3 trials, 452 participants), in the cohort studies, participants who used mefloquine were statistically significantly more likely to experience dizziness (RR = 1.80, 95%CI 1.29–2.49; 3 studies, 1,901 participants) than those who used placebo or no drug. No differences were observed between mefloquine and placebo groups for vertigo in either trials or cohort studies. Cohort study comparisons between mefloquine and doxycycline users found no differ- ences for headache or dizziness. None of the randomized controlled trials reported on the psychiatric symptoms of abnormal dreams, insomnia, anxiety, depressed mood, or abnormal thoughts and perceptions (psychosis). Participants in cohort studies who received mefloquine were more likely than participants who did not take prophylaxis to experience abnormal dreams (RR = 2.35, 95%CI 1.15–4.80; 2 ­ tudies, 931 participants) and s insomnia (RR = 1.46, 95%CI 1.06–2.02; 2 studies, 931 participants). Effects on anxiety (RR = 1.21, 95%CI 0.67–2.21; 2 studies, 931 participants), depressed mood (RR = 2.43, 95%CI 0.65–9.07; 3 studies, 1,901 participants), and abnormal thoughts or perceptions (RR = 5.77, 95%CI 0.79–42.06; 1 study, 970 participants) were not consistent across studies and did not reach standard levels of statistical significance. Findings from trials and cohort studies that used A/P as a comparator were similar, with mefloquine users statistically significantly more likely to report abnormal dreams, insomnia, anxiety, and depressed mood, although it should be noted that all of the effect estimates were quite imprecise. Using the six cohort studies that used doxycycline as a comparator, mefloquine users were more likely to report abnormal dreams (RR = 10.49, 95%CI 3.79–29.10; 4 studies, 2,588 participants), insomnia (RR = 4.14, 95%CI 1.19–14.44; 4 studies, 3,212 partici- pants), anxiety (RR = 18.04, 95%CI 9.32–34.93; 3 studies, 2,559 participants), and depressed mood (RR = 11.43, 95%CI 5.21–25.07; 2 studies, 2,445 participants), but the pooled effect estimates were very imprecise. Additionally, 15 episodes of abnormal thoughts and perceptions were reported among mefloquine users and none among doxycycline users in the cohort studies reporting adverse events. In the single trial included and the large retrospective health care record analyses, there were either no differences between groups, or doxycycline users were more likely to experience psychiatric symptoms. Overall, the authors concluded that people taking mefloquine are more likely to have abnormal dreams, insomnia, anxiety, and depressed mood during travel than people who take A/P (moderate- certainty evidence) or doxycycline (very low-certainty evidence). Mefloquine recipients were more likely to experience nausea than placebo recipients for both trials (RR = 1.35, 95%CI 1.05–1.73; 2 trials, 244 participants) and cohort studies (RR = 1.85, 95%CI 1.42–2.43; 3 studies, 1,901 participants), but there was no difference between groups for vomiting, abdominal pain, or d ­ iarrhea. For both trials and cohort studies, when mefloquine users were com- pared with A/P users, mefloquine users were statistically significantly more

MEFLOQUINE 111 likely to experience nausea, but there was no statistically significant difference for vomiting, abdominal pain, or diarrhea. Based on data from cohort studies, mefloquine users were less likely than doxycycline users to report dyspepsia (RR = 0.26, 95%CI 0.09–0.74; 5 studies, 5,104 participants), vomiting (RR = 0.18, 95%CI 0.12–0.27; 4 studies, 5,071 participants), nausea (RR = 0.37, 95%CI 0.30–0.45; 5 studies, 2,683 participants), and diarrhea (RR = 0.28, 95%CI 0.11– 0.73; 5 ­ tudies, 5,104 participants). No difference between mefloquine users and s doxycycline users was found for abdominal pain (RR = 0.30, 95%CI 0.09–1.07; 4 studies, 2,569 participants). The authors stated that the estimates for dyspepsia and vomiting were given low or very low certainty of evidence. Other symptoms were also included when available. Based on one cohort study of 197 partici- pants, mefloquine users were more likely than those who were given placebo to experience pruritus (RR = 6.71, 95%CI 1.58–28.55), although the estimate was imprecise. Pruritus was not statistically different between mefloquine users and placebo or non-drug users in trials (RR = 0.86, 95%CI 0.60–1.24; 3 trials, 609 participants). Based on the data from cohort studies, mefloquine users were less likely than doxycycline users to report photosensitivity (RR = 0.08, 95%CI 0.05–0.11) and vaginal thrush (RR = 0.10, 95%CI 0.06–0.16), but for both of these results the evidence was considered to be very low certainty. No differences were observed between mefloquine and placebo groups for visual impairment in either trials or cohort studies. Authors noted that comparisons of mefloquine with chloroquine added no new information and that subgroup analysis by study design, duration of travel, and military versus non-military participants provided no conclusive findings. Post-Cessation Adverse Events A total of 1,577 abstracts or titles were identified by the committee for inclu- sion for mefloquine. After screening, 489 abstracts and titles remained, and the full text for each was retrieved and reviewed to determine whether it met the committee’s inclusion criteria, as defined in Chapter 3. The committee reviewed each article and identified 11 epidemiologic studies that included some mention of adverse events that occurred ≥28 days post-cessation of mefloquine (DeSouza, 1983; Eick-Cost et al., 2017; Laothavorn et al., 1992; Meier et al., 2004; Schlagen- hauf et al., 1996; Schneider et al., 2013, 2014; Schneiderman et al., 2018; Schwartz and Regev-Yochay, 1999; Tan et al., 2017; Wells et al., 2006). A table that gives a high-level comparison (study design, population, exposure groups, and outcomes examined by body system) of each of the 11 epidemiologic studies that examined the use of mefloquine and that met the committee’s inclusion criteria is presented in Appendix C. Other identified articles are cited in the background, case reports and selected subpopulations, and biologic plausibility sections as relevant.

112 LONG-TERM HEALTH EFFECTS OF ANTIMALARIAL DRUGS Military and Veterans Using DoD administrative databases, Eick-Cost et al. (2017) performed a retrospective cohort study among 367,840 active-duty service members who filled at least one prescription for an antimalarial drug for prophylaxis between 2008 and 2013: 36,538 were prescribed mefloquine, 318,421 doxycycline, and 12,881 A/P. The primary study objective was to assess and compare the risk of incident and recurrent International Classification of Diseases, Ninth Revision, Clinical Modi- fication (ICD-9-CM)–coded neurologic and psychiatric outcomes (adjustment dis- order, anxiety disorder, depressive disorder, posttraumatic stress disorder [PTSD], psychoses, suicide ideation, paranoia, confusion, tinnitus, vertigo, convulsions, hallucinations, insomnia, and suicide) that were reported at medical care visits dur- ing concurrent use plus 365 days after the end of the prescription for mefloquine, doxycycline, and A/P. Although the authors did not report results for the period of ≥28 days post-cessation of antimalarial drug use, they stated that they performed several sensitivity analyses, including one in which the risk period was restricted to 30 days post-prescription. The results of that analysis were summarized in the text as follows: “However, none of these analyses significantly changed the results of the study and are therefore not reported” (p. 161). This statement implies (but does not show directly) that similar findings to those reported would be seen if the data were restricted to the period of relevance to the committee’s definition of persistence (i.e., ≥28 days after cessation of exposure). The committee was unsure how to interpret that sentence reporting that the results did not change significantly (statistical significance, precision of effect estimates, number of diagnoses, etc.), but given that the authors performed sensitivity analyses, the number of methodo- logic strengths, including strong measurement of relevant outcomes conducted in the target population, the committee chose to include it, despite the ambiguity in the language. If an individual had multiple prescriptions over the follow-up period, risk periods were merged. Doxycycline and A/P prescriptions were excluded if the service member previously or concurrently received mefloquine. Mefloquine risk periods were censored if an individual received a prescription for a differ- ent antimalarial. Analyses were stratified by deployment and psychiatric history. Models were adjusted for age, sex, service, grade, and year of prescription start; analyses of deployed service members also controlled for location and combat exposure. Mefloquine recipients had primarily served in the Air Force (58%), held a rank of senior enlisted (47%), and most had had prescriptions filled prior to 2010 (75%). Among the deployed service members, 29% of the individuals who had received mefloquine reported having had combat exposure (compared with 43% for ­ oxycycline and 21% for A/P). d With few exceptions, adjusted incident rates were higher among the deployed than among the nondeployed for mefloquine as well as for the other antimalarial drugs considered. Effect estimates of neurologic and psychiatric outcomes for ­ oxycycline and A/P are reported in those respective chapters. For mefloquine users d

MEFLOQUINE 113 the highest incident rates among both the deployed and nondeployed were for adjust- ment disorder (28.66 versus 18.75 per 1,000 person-years, respectively), ­ ollowed f by insomnia (15.78 versus 10.09 per 1,000 person-years, respectively) and anxiety disorder (14.51 versus 9.28 per 1,000 person-years, ­ espectively). Incident depres- r sive disorder (12.46 versus 8.59 per 1,000 person-years, respectively) and vertigo (12.19 versus 11.90 per 1,000 person-years, respectively) were also higher among the deployed group. The incidence of tinnitus, however, was higher among the nondeployed than among the deployed (14.02 versus 13.44 per 1,000 person-years, respectively) as was the case for convulsions, psychoses, suicide, and confusion. Among those prescribed mefloquine, the incidence rate of PTSD was 11.08 per 1,000 person-years in the deployed group and 5.05 per 1,000 person-years in the nondeployed group. Adjusted incidence rate ratios (IRRs) comparing mefloquine to doxycycline by deployment status found that among the deployed, the only statisti- cally significant difference between the two drugs was for anxiety disorder (IRR = 1.12, 95%CI 1.01–1.24). When mefloquine and doxycycline users were compared among the nondeployed, the outcomes of adjustment dis­ rder (IRR = 0.69, 95%CI o 0.60–0.80), insomnia (IRR = 0.67, 95%CI 0.56–0.81), anxiety disorder (IRR = 0.70, 95%CI 0.57–0.86), depressive disorder (IRR = 0.68, 95%CI 0.55–0.84), vertigo (IRR = 0.52, 95%CI 0.31–0.88), and PTSD (IRR = 0.69, 95%CI 0.52–0.91) all showed a statistically significantly lower risk for mefloquine users but no differences were found for the other outcomes. Adjusted IRRs comparing mefloquine with A/P by deployment status found that the risk of tinnitus among both the deployed (IRR = 1.81, 95%CI 1.18–2.79) and the nondeployed (IRR = 1.51, 95%CI 1.13–2.03) was statistically significantly elevated among those taking mefloquine. No other outcomes were statistically significantly different between deployed mefloquine and A/P users. Among the nondeployed, the only other statistically significant difference between mefloquine and A/P users was for PTSD (IRR = 1.83, 95%CI 1.07–3.14). A subsequent analysis restricted the population to the first mefloquine or ­ oxycycline d prescription per individual and included individuals with a prior history of a neu- rologic or psychiatric diagnosis. Incidence rates and IRRs for each neurologic and psychiatric outcome were compared, stratified by those with and without a prior neurologic or psychiatric diagnosis. In total, 5.9% of those prescribed mefloquine and 9.2% of individuals prescribed doxycycline had had at least one neurologic or psychiatric diagnosis in the 365 days before the prescription, suggesting that those with a psychiatric disorder were less likely to be prescribed mefloquine, consistent with the contra­ndications of the drug. A diagnosis of PTSD was recorded for 131 i (0.4%) individuals in the mefloquine group and for 2,671 (0.8%) individuals in the doxycycline group in the 365 days prior to the first antimalarial prescription. For both the mefloquine and doxycycline groups, individuals with a neurologic or psy- chiatric diagnosis in the year preceding the prescription had statistically significantly elevated risks for a subsequent diagnosis of the same condition for all conditions reported (adjustment disorder, anxiety, insomnia, depressive disorder, PTSD, tin- nitus, vertigo, and convulsions) than individuals without a diagnosis in the prior

114 LONG-TERM HEALTH EFFECTS OF ANTIMALARIAL DRUGS year. However, when the IRRs contrasting mefloquine and doxycycline users were compared within strata of those with and without prior neurologic or psychiatric diagnoses, there were no statistically significant differences between mefloquine and doxycycline for any of the conditions, including PTSD (bootstrap RRR = 1.14, 95%CI 0.78–1.65). The committee found this study to be well designed. Important factors that increased the study quality were the large sample size; the use of an administrative data source, which provides some degree of objectivity; and the careful consid- eration of potential confounding variables, including demographics, psychiatric history, and military characteristics of deployment and combat exposure. Because neurologic and psychiatric diagnoses occurring during current and recent use were analyzed together without distinguishing between events that occurred within 28 days of antimalarial use and those that occurred ≥28 days post-cessation, the study provides no quantitative information regarding the persistence of most events other than the notation in text that results did not change when restricted to the post-cessation period. The use of administrative data provided a standard, consistent method to capture filled prescriptions and medical diagnoses through the use of ICD-9-CM codes. However, filled prescriptions do not equate to adher- ence to the drug regimen. Moreover, if the antimalarials were provided to entire units as part of force health protection measures, the use of these drugs would not be coded in individual records. Whereas the use of medical diagnoses is likely to be more reliable for the outcomes than self-report, the data are dependent on the accuracy of the coding, and there was no validation of the diagnoses recorded in the administrative databases, and symptoms or events that did not result in a medical visit or diagnosis would have been missed. For PTSD diagnoses, there was no information about when the index trauma occurred. Given the largely decreased risks and null results reported for the study, this implies null results would be found for the period of interest, but the data were not presented to examine this directly. Schneiderman et al. (2018) conducted a retrospective observational analysis of self-reported health outcomes associated with use of antimalarial drugs in a cohort of U.S. veterans who had responded to the 2009–2011 National Health Study for a New Generation of U.S. Veterans (referred to as the NewGen Study). The NewGen Study is a population-based survey that sampled 30,000 veterans who had been deployed to Iraq or Afghanistan between 2001 and 2008 and 30,000 nondeployed veterans who had served during the same time period; it included a 20% oversampling of women. The survey was conducted using mail, telephone, and web-based collection and yielded a response rate of only 34.3%. For this particular analysis, 19,487 participants were included who had self-reported their history of antimalarial medication use, and the use was grouped for the analysis by drug (mefloquine, chloroquine, doxycycline, primaquine, mefloquine in com- bination with other drugs, other antimalarials, and not specified) or no antimalarial use. Health outcomes were self-reported using standardized instruments: the Medical Outcomes Study 12-item Short Form (SF-12) for general health status,

MEFLOQUINE 115 PTSD Checklist–Civilian version (PCL-C), and the Patient Health Question- naire. These instruments yielded scores that were dichotomized for analysis on composite physical health, composite mental health (above or below the U.S. mean), PTSD (above or below screening cutoff), thoughts of death or self-harm, other anxiety disorders, and major depression. Potential confounders included in the multivariable analysis were the branch of service, sex, age, education, race/ ethnicity, household income, employment status, marital status, and self-reported exposure to combat. Responses were weighted to account for survey non-response. Most veterans reported no antimalarial drug exposures (61.4%, n = 11,100), and these served as the referent group. Focusing first on those veterans who had been deployed (n = 12,456), of those who reported use of an antimalarial drug (n = 6,650), 307 (4.4% weighted) reported only using mefloquine, and 425 (6.0% weighted) reported using mefloquine and another antimalarial. Among the non- deployed (n = 7,031), 39 (2.2% weighted) used mefloquine alone, and 52 (2.8% weighted) used mefloquine and another antimalarial. The deployed mefloquine- plus-another-antimalarial users reported the highest prevalence of positive screens for PTSD (20.0%), other anxiety disorders (15.3%), and major depression (12.5%) compared with mefloquine alone and with the other antimalarial drug groups in the deployed and nondeployed strata. Descriptive statistics indicated that the deployed mefloquine users reported greater frequencies of mental health diagnoses than non- deployed mefloquine users—PTSD (14.2% versus 7.5%), other anxiety disorders (10.8% versus 5.7%), major depression (9.3% versus 3.3%), and thoughts of death or self-harm (14.0% versus 7.1%)—but no statistical inferences were presented. In the adjusted logistic regression models with all covariates considered (includ- ing demographics, deployment, and combat exposure), the use of mefloquine alone was not associated with an increased risk for any of the health outcomes when compared with nonuse of antimalarial drugs: composite mental health score (OR = 0.87, 95%CI 0.66–1.14), composite physical health score (OR = 0.96, 95%CI 0.73–1.26), PTSD (not adjusted for combat exposure) (OR = 0.86, 95%CI 0.58–1.27), thoughts of death or self-harm (OR = 1.21, 95%CI 0.80–1.82), other anxiety (OR = 0.77, 95%CI 0.49–1.22), and major depression (OR = 0.74, 95%CI 0.46–1.20). Results were similar and not statistically significant for mefloquine use in combination with other antimalarials for analyses restricted to the deployed subset of veterans. An additional analysis was performed on the six health indica- tors or outcomes stratified by antimalarial exposure and a four-level measure of combat exposure intensity. The weighted prevalence estimates seem to indicate an increasing prevalence of disorders with increasing combat exposure intensity, but it is challenging to interpret the results or to compare across antimalarial expo- sures given the small numbers in some cells and the lack of confidence intervals or hypothesis tests. This analysis of the NewGen survey is highly relevant to the question of whether there are effects of mefloquine use that persist after the cessation of drug use. The study is large enough to generate moderately precise measures of associa-

116 LONG-TERM HEALTH EFFECTS OF ANTIMALARIAL DRUGS tion, the specific drugs were assessed, the outcomes were based on standardized instruments (although not face-to-face diagnostic interviews), important covariates of deployment and combat exposure were considered in addition to demographics and other military characteristics, and the data were appropriately analyzed. The number of mefloquine-only users in this sample was relatively small (346 of anti- malarials users). It is noteworthy that adjustment for combat exposure consistently reduced the measures of association, potentially indicating the strong confounding that can exist due to combat exposure. Although the time period of drug use and the timing of health outcomes was not directly addressed, given that the popula- tions were all veterans who had served between 2001 and 2008 and that the survey was not administered until 2009–2011, it is reasonable to assume that antimalarial drug use had ceased some time before. Nonetheless, the study could not address explicitly the health experiences during use and in specific time intervals follow- ing the cessation of use. There are a number of methodologic concerns that limit the strength of this study’s findings. The low response rate of 34% raises concerns of non-response bias, but responses were weighted to account for non-response. Selective participation by both antimalarial drug use history and health status would be required to introduce bias. The accuracy of self-reported antimalarial drug use in this population is unknown. Although self-reported information has some advantages over studies based on prescriptions in that the individual recalls using the drug, validation of the reported drug and information on adherence is not captured. Self-reported health experience is subject to the usual disadvantages of recall bias and bias of reporting subjective experience without independent expert assessment; however, by using standardized assessment tools, these biases may have been circumvented to some extent. The Wells et al. study was commissioned in 2004 by the assistant secretary of defense in response to concerns within DoD about adverse health outcomes associated with the use of mefloquine (DoD, 2009a). Wells et al. (2006) used DoD administrative databases and a retrospective observational design to examine U.S. active-duty service members who had been prescribed mefloquine (minimum seven tablets) and deployed at some time in calendar year 2002 (n = 8,858). Their health experience was compared with that of U.S. service personnel assigned to Europe or Japan (n = 156,203), who did not use antimalarials. This comparison group was intended to control for being healthy enough to be stationed overseas, but this group was not considered to be “deployed” in the same manner as to an operational theater or combat zone. A second control group consisted of active- duty service members who were deployed for 1 month or longer during 2002 but had not been prescribed mefloquine or other commonly used antimalarial drugs (n = 232,381). Although the use of two comparison groups can be helpful when results are consistent, it is important that both are similar to the exposed group. The demographic and military characteristics of the Europe- and Japan-stationed individuals differed substantially from those of the deployed individuals. Health outcomes were based on hospitalization records within the military health care

MEFLOQUINE 117 s ­ ystem and the corresponding ICD-9-CM codes for diagnoses by body system, including a number of physical and mental health conditions. The use of hospital- izations indicates adverse events of a greater severity for reported disorders than may be experienced by other populations of mefloquine users. The association between mefloquine exposure and hospitalization was analyzed through Cox proportional hazards modeling, with the follow-up time beginning on return from deployment (with or without mefloquine exposure). Adjustment was made for sex, age, race/ethnicity, service branch, marital status, rank, occupation, and history of hospitalization in 2001. Compared with those nondeployed service members who were assigned to Europe or Japan, those prescribed mefloquine during their deployment had a statistically significantly lower risk of hospitalization for any cause (HR = 0.47, 95%CI 0.39–0.56) as well as for reasons specific to the diges- tive system (HR = 0.52, 95%CI 0.34–0.79), for reasons specific to the respiratory system (HR = 0.44, 95%CI 0.23–0.86), for musculoskeletal disorders (HR = 0.68, 95%CI 0.47–0.98), for ill-defined conditions (HR = 0.24, 95%CI 0.16–0.37), and for injury and poisoning (HR = 0.63, 95%CI 0.47–0.84). No statistically significant differences were found between mefloquine users and those assigned to Europe or Japan for hospitalizations related to mental disorders (HR = 0.76, 95%CI 0.55–1.07) or for disorders of the nervous system (HR = 0.58, 95%CI 0.26–1.32), the circulatory system (HR = 0.61, 95%CI 0.31–1.18), blood and blood-forming organs (HR = 0.51, 95%CI 0.19–1.36), or skin and subcutaneous tissues (HR = 0.88, 95%CI 0.43–1.80). The hazard ratios comparing mefloquine users with deployed nonusers of antimalarials yielded null results across the range of all outcomes reported, including hospitalization for any cause (HR = 0.94, 95%CI 0.79–1.12), mental disorders (HR = 1.23, 95%CI 0.87–1.72), or disorders of the nervous system (HR = 0.76, 95%CI 0.34–1.73), digestive system (HR = 0.90, 95%CI 0.60–1.37), circulatory system (HR = 0.69, 95%CI 0.35–1.34), blood and blood-forming organs (HR = 0.65, 95%CI 0.24–1.74), or skin and subcutaneous tissues (HR = 1.31, 95%CI 0.64–2.69). Hospitalizations related to categories of infections; neoplasms; disorders of endocrine, nutritional, or metabolism; and dis- orders of the genitourinary system were also examined between mefloquine users and the two reference groups but none reached statistical significance. A total of 37 hospitalizations for mental disorders as a category were reported for mefloquine users, and when hospitalizations due to specific psychiatric outcomes were consid- ered, there were no cases of somatoform disorders, 6 cases each of mood disorders and anxiety disorders, 1 case of PTSD, 19 cases of substance use disorders, 7 cases of personality disorders, 13 cases of adjustment reactions, 4 cases of mixed syn- dromes, and 20 cases of “other disorders” among mefloquine users. A comparison of these rates with those of the two reference groups of service members resulted in imprecise and null estimates. Only six hospitalizations due to nervous system disorders were reported for mefloquine users, and comparisons with both reference groups showed that mefloquine users had no statistically significant difference in risk for nervous system disorders as a group. When hospitalizations due to specific

118 LONG-TERM HEALTH EFFECTS OF ANTIMALARIAL DRUGS neurologic outcomes were considered, among those receiving mefloquine there were no cases of nystagmus or dizziness and giddiness, one case of vertiginous syndromes, and three cases of migraine, which resulted in wide, imprecise, and null effect estimates when these rates were compared with those of the two refer- ence groups of service members. Deployed mefloquine users had numerically higher rates than deployed nonusers, but no comparisons reached statistical signifi- cance, and all effect estimates of individual diagnoses had less precision than when reported by organ system. For example, only one diagnosis of PTSD was reported in the mefloquine user group, compared with 29 diagnoses in the deployed non- user group (HR = 1.66, 95%CI 0.21–12.85) and 38 diagnoses in the Europe/Japan group (HR = 0.79, 95%CI 0.11–5.91). The only statistically significant difference found between mefloquine users and those assigned to Europe or Japan was for mood disorders (HR = 0.37, 95%CI 0.15–0.90). Overall, this is a well-designed study that was likely adequately powered to detect moderate differences. Because the follow-up of the mefloquine users began at the time of their return from deployment, it is reasonable to assume that these results largely reflected their experiences following cessation of exposure of vary- ing duration. Nonetheless, the results for varying time intervals following cessa- tion of use (or time since return from deployment) were not presented. Although the use of two comparison groups can be helpful when the results are consistent, it is important that both be similar to the exposed group. The demographic and military characteristics of the Europe- and Japan-stationed individuals differed substantially from the deployed individuals, suggesting that this was not an appro- priate comparison group. With regard to exposure, a prescription is not the same as having actually taken the drug or having taken it as indicated, creating the potential for misclassification. A reasonable set of covariates was used to adjust effect esti- mates, in particular the sociodemographic covariates. However, combat exposure was not specifically addressed, and although deployment may have been assumed to be a surrogate for combat, the lack of control for combat exposure itself is a limitation. The health outcomes were systematically and objectively ascertained but would reflect only the most severe experiences requiring hospitalization, and for this reason, the number of cases was generally small (i.e., 135 mefloquine users were hospitalized for any cause). Because the diagnoses were based on clinical encounters, the PTSD diagnoses are presumably linked to an index trauma crite- rion A event. Most people who experience mental health disorders would not be hospitalized, and the small number of specific neurologic and psychiatric cases reported further limits the generalizability of these results. U.S. Peace Corps Tan et al. (2017) conducted a retrospective observational Internet-based sur- vey of 8,931 (11% response rate) returned Peace Corps volunteers (who had served during 1995–2014) to compare the prevalence of selected health conditions after

MEFLOQUINE 119 Peace Corps service between those who reported taking malaria prophylaxis (n = 5,055, 56.6%) and those who did not. The reported initial antimalarial prophylactic prescriptions were mefloquine (n = 2,981; 59.0%), A/P (n = 183; 3.6%), chloro- quine (n = 674; 13.3%), doxycycline (n = 831; 16.4%), and 386 (7.6%) “other” prophylactic medications. In addition to questions on malaria prophylaxis (type, regimen, duration, and adherence), the survey included questions about the coun- try of service, type of assignment, and whether malaria prophylaxis was required at the assigned site. Respondents were also asked to report medical diagnoses made by a health care provider before, during, and after service in the Peace Corps and to answer questions about medications used before, during, or after Peace Corps service; family history of disease and psychiatric illness; psychiatric history prior to exposure; and alcohol consumption. In total, more than 40 disease outcomes were examined for associations with each antimalarial, including derived out- comes of major depressive disorder, bipolar disorder, anxiety disorder, insomnia, psychoses, and cancers. Outcomes were grouped by system (neuropsychologic, cardiac, ­ phthalmologic, dermatologic, reproductive, and gastrointestinal) or class o (infectious, hematologic/oncologic) and within each group several diagnoses were listed. “Any psychiatric outcome” included all reported psychiatric diagnoses both derived and those reported as individual diagnoses, including schizophrenia, obsessive-compulsive disorder, and “other.” Neuropsychologic disorders were presented as a category that separately included dementia, migraines, seizures, tinnitus, vestibular disorder, “other” neurologic disorder, and “any” neurologic disorder. Among those who had reported any use of mefloquine, the prevalence of any psychiatric disease following Peace Corps service was 15.9%, which was lower than the prevalence for people who had not used mefloquine (18.8%). Among people with a prior psychiatric illness, fewer reported the use of meflo- quine than among those without a prior psychiatric illness (16.2% versus 44.0%, respectively), which would be expected since prior psychiatric illness is a contra­ indication of mefloquine. Estimates adjusted for a prior history of psychiatric disease and a family history of psychiatric disease indicated that mefloquine users had a higher likelihood of having any psychiatric diagnosis post-service rela- tive to individuals who did not take mefloquine (prevalence ratio = 1.15, 95%CI 1.07–1.23). When those with a prior psychiatric history were excluded from the analysis, there was no difference in the prevalence of any psychiatric outcomes between those who had used mefloquine and those who had not (prevalence ratio = 1.07, 95%CI 0.95–1.21), but the results were not presented separately for those with a prior psychiatric history. No difference in the prevalence of any psychiatric outcomes was found when comparing prolonged duration of mefloquine use with any other antimalarial. The authors reported that there were no differences in the prevalence of several diagnoses that have previously been reported as adverse events and feared adverse events associated with mefloquine use, including ves- tibular dysfunction, neurologic disorders, insomnia, arrhythmias, other cardiac diseases, and ophthalmologic disorders (a category that included macular degen-

120 LONG-TERM HEALTH EFFECTS OF ANTIMALARIAL DRUGS eration, retinopathy, and “any” ophthalmologic disorder), although specific effect estimates were not shown. No other differences for other outcomes were reported. The study had many limitations—primarily stemming from its design as an Internet-based survey of people with email addresses on file. The response rate was low (11%), the authors relied on self-report for both exposure and outcome information and the timing of each, and for some participants the time between exposure and the survey was many years. Most comparisons were between spe- cific drug exposure (i.e., mefloquine, chloroquine, doxycycline, A/P, other) and no exposure to the drug of interest, so that the comparison group for each antimalarial was a mixture of those who did not report taking any antimalarials and those who reported taking antimalarial drugs other than the one being examined. Overall, there were few details of the limited analyses presented, making it difficult to understand the groups that were being compared, how they differed with respect to important covariates, and what variables were included in the models. The reliance on self-report, often years (range 2–20 years) after exposure, introduces several potential biases (selection bias, recall bias, and confounding bias), with inadequate information to determine the likely impact or direction of the potential biases act- ing in this study. While the use of self-reported diagnoses that were specified to be those made by a medical professional to ascertain health outcomes was arguably a better method than using a checklist of symptoms, the outcomes were not vali- dated against any objective information. The results presented in this study do not support the presence of persistent or latent health effects, or incident neurologic or psychiatric effects specifically, post-cessation of mefloquine, but the design limitations of this study are such that any evidence provided by this study is weak. Travelers Three retrospective observational studies of travelers (Meier et al., 2004; Schneider et al., 2013, 2014) were conducted using data from the UK-based ­ eneral Practice Research Database (GPRD)—which has since changed names G to the Clinical Practice Research Datalink—to assess the incidence and compare the odds of developing first-time neurologic, psychiatric, or eye disorders in individuals using mefloquine compared with other antimalarial drugs for malaria prophylaxis. The Clinical Practice Research Datalink, which has been active for more than 30 years, collects de-identified patient data from a network of general practitioner practices across the United Kingdom for use in public health research and clinical studies, which have included investigations of drug safety, the use of medications, health care delivery, and disease risk factors (CPRD, 2019). While the specific outcomes examined (neurologic, psychiatric, and eye disorders) dif- fered by study, the general methodology was the same. Using the GPRD, investi- gators identified individuals who had at least one prescription for mefloquine, A/P, doxycycline, or chloroquine and/or proguanil in the time period of interest and who had a pre-travel consultation within 1 week of the date of the prescription that

MEFLOQUINE 121 included specific codes indicating that the prescription was for malaria prophy- laxis. The start of follow-up was the date of receipt of the first prescription for an individual. Current use was defined as the period between the date a prescription was started and 1 week after the end of the prescription period. Current exposure time was calculated differently for each antimalarial drug because the regimen for each of the antimalarial drugs differs. Investigators based their assessment on the number of tablets recorded by the general practitioner and calculated the assumed exposure time for each of the antimalarial drugs being investigated. For meflo- quine, the current exposure time (in days) was the number of tablets multiplied by 7 plus 28 days. Investigators added 90 days to each exposure to capture events that occurred during travel that came to the attention of the general practitioner after the traveler returned to the United Kingdom; this timeframe was termed “recent use” in Meier et al. (2004). Recent use included periods both relevant to the committee’s charge (days 28–89) as well as time periods that the committee considered exclusionary (days 7–27). Past use started at day 90 (Meier et al., 2004) or day 91 (Schneider et al., 2013, 2014) and ended at a maximum of 540 days after the end of current exposure, reflecting a time period pertinent to the commit- tee’s assessment. Non-exposed people served as controls and had no antimalarial prescription during the study period or during 540 days after their pre-travel con- sultation, which also served as the date of the start of their follow-up. Participants were required to have at least 12 months of information on prescribed drugs and medical diagnoses before the first prescription date for an antimalarial or, for the non-exposed controls, before their travel consultation. An additional inclusion criterion required participants to have recorded medical activity (diagnoses or drug prescriptions) after receiving a prescription to ensure that only individuals who returned to the United Kingdom were included. A nested case–control analysis was also performed for a subset of the population in which up to six controls (who did not develop an outcome of interest during follow-up) were randomly selected per case; controls were matched to cases on age, sex, general practice, and calendar time (by assigning each control to the same index date as their matched case). Overall, the design of these large, retrospective studies allowed for adequate power to detect differences in outcomes and for a uniform collection of exposures and outcomes that were not subject to recall bias. The nested case–control compo- nent allowed for the control of important covariates. Relying on recorded drug pre- scriptions to determine exposure ensured that the assessment was applied equally to all exposure groups; however, as with any study that relies on administrative databases, prescriptions are not a surrogate for adherence. Outcome assessment was uniform for all exposure groups and based on medical care visits coded in a database designed for both practice and research and with validated outcomes. Events that did not result in a medical care visit or that occurred outside of the national health care system would have been missed, and there may also have been some differences between the travelers who traveled to malaria-endemic areas versus areas that are not endemic for malaria, which could have led to some

122 LONG-TERM HEALTH EFFECTS OF ANTIMALARIAL DRUGS apparent differences in outcomes between the groups. However, it is unlikely that this would have resulted in differential selection bias. Additional strengths and limitations that are study specific are noted within each study summary. Meier et al. (2004) used the GPRD to assess the incidence of depression (n = 505), psychosis (n = 16), panic attacks (n = 57), and death by suicide (n = 2) in recent users (90 days following current use) of mefloquine compared with both current users (during active use) of proguanil and/or chloroquine or doxycycline and past users (90–540 days) of any of these antimalarials. The study popula- tion encompassed 35,370 individuals aged 17–79 years who used antimalarials between January 1990 and December 1999: 16,491 mefloquine users, 16,129 chloroquine and/or proguanil users, and 4,574 doxycycline users (some indi­ viduals used multiple drugs). Investigators calculated the incidence of the four prespecified psychiatric outcomes during current, recent, and past use (people with prior diagnoses of the four psychiatric outcomes or alcoholism were excluded), and they also performed a nested case–control analysis in which both cases and controls had no history of the outcomes of interest prior to use of an antimalarial. The incidence rates of first-time diagnoses were calculated using person-years and were adjusted for age, gender, and calendar year. The incidence rate of first-time depression diagnosis did not differ between recent mefloquine users and all past users of antimalarials (RR = 1.0, 95%CI 0.7–1.4). In the nested case–control analy- sis, there was no difference in the odds of depression between recent mefloquine users and all other users combined after adjustment for age, gender, year, general practice, smoking status, and BMI (OR = 0.7, 95%CI 0.5–1.1). Only one case of incident psychosis was reported with recent mefloquine use, resulting in impre- cise effect estimates in both the incident rate analysis and the nested case–control analysis. Regarding panic attacks, the incidence rate of a first-time diagnosis was not statistically significantly different between recent users of mefloquine and past users of antimalarials (RR = 2.4, 95%CI 1.0–5.7). This result remained nonstatis- tically significant in the nested case–control analysis after adjustment for smok- ing status and BMI (OR = 2.3, 95%CI 0.8–6.1). For current users of mefloquine compared with all past users of antimalarials and adjusted for smoking status and BMI, the odds of panic attack were statistically significantly elevated (OR = 2.7, 95%CI 1.1–6.5). The authors estimated that one psychosis episode and three panic attack events could be expected per 6,700 mefloquine courses. This was a large retrospective study that found no increase in depression associated with current or recent use of mefloquine compared with use of proguanil/chloroquine or all past users of antimalarials. The sample size was more limited for studying panic attacks and psychosis, leading to very imprecise estimates for those outcomes. Since current and recent use were analyzed separately, persistent outcomes were difficult to determine. Schneider et al. (2013) used the GPRD to estimate the incidence of anxiety, stress-related disorders, or psychosis (n = 952); depression (n = 739); epilepsy (n = 86); or peripheral neuropathy (n = 56) in individuals (aged ≥ 1 year) with a

MEFLOQUINE 123 pre-travel consultation and at least one prescription for mefloquine (n = 10,169), A/P (n = 28,502), or chloroquine and/or proguanil (n = 2,904) for malaria chemo­ prophylaxis, or no antimalarial prescription (but who had a travel consultation) (n = 41,573) between January 1, 2001, and October 1, 2009 (conducted approxi- mately 10 years after Meier et al., 2004). Individuals were excluded if there was a record of a diagnosis of malaria prior to the start of antimalarial drug use; a his- tory of cancer, alcoholism, or rheumatoid arthritis; or a diagnosis of an outcome of interest prior to a prescription for an antimalarial or, for the unexposed group, any of those diagnoses prior to the date of the pre-travel clinic visit. The date of the diagnosis of the first neurologic or psychiatric disorder was the index date for each case. Investigators estimated the incidence of the specified neurologic and psychiatric outcomes that occurred up to 540 days following current use of mefloquine compared with other antimalarials and with no use of antimalarials. Although 15.3% of the population was ≤18 years and the reported number of cases of each outcome was reported by age group, the authors presented only the associations between drugs and health outcomes for the total population (children and adults). Despite that limitation, the committee presents the results as reported because a relatively small proportion of the population was under age 18 years, and the results should approximate the associations that would have been found for adults only. The overall incidence rates for anxiety, stress-related disorders, or psychosis (presented as a group) and depression were lower for mefloquine users than for users of A/P, chloroquine and/or proguanil, or no antimalarial drug. A nested case–control analysis was also conducted in which investigators catego- rized subjects into current (use of drug plus 90 days post-cessation) or past-use (91–540 days post-cessation) exposure groups and controlled for age, sex, calendar time, general practice, smoking, and BMI. Individuals who did not develop the outcomes of interest during the follow-up period formed the control group, and six controls per case matched on sex, year of birth, general practice, and calendar time were selected. Over the study period, a total of 14 mefloquine users were diagnosed with incident epilepsy, 6 of whom were current users and 8 of whom were past users. Among the eight mefloquine users with incident neuropathies, five were current users and three were past users. A total of 99 mefloquine users (42 current users and 57 past users) were diagnosed with incident anxiety or stress- related disorders or psychosis, and 68 mefloquine users (16 current users and 52 past users) were diagnosed with incident depression. Comparing current users of mefloquine (which included a mixture of nonrelevant [during use to 27 days post- use] and relevant [days 28–90 post-use] time periods) with travelers who did not use any antimalarial prophylaxis, after adjustment for smoking and BMI, the odds of developing anxiety, stress-related disorders, or psychosis (OR = 0.76, 95%CI 0.53–1.08); epilepsy (OR = 0.85, 95%CI 0.32–2.20); or peripheral neuropathy (OR = 2.27, 95%CI 0.73–7.06) were no greater for current mefloquine users. Current mefloquine users had statistically significantly lower odds of developing depression than non-antimalarial users (OR = 0.32, 95%CI 0.19–0.54). The odds

124 LONG-TERM HEALTH EFFECTS OF ANTIMALARIAL DRUGS of developing anxiety, stress-related disorders, or psychosis (OR = 0.68, 95%CI 0.51–0.92) and depression (OR = 0.68, 95%CI 0.50–0.94) were statistically sig- nificantly lower in past users of mefloquine than in those who did not use an anti- malarial, but the odds of epilepsy (OR = 0.61, 95%CI 0.27–1.40) and neuropathy (OR = 0.67, 95%CI 0.18–2.43) were no different. When anxiety, psychosis, pho- bia, and panic attack were analyzed as separate outcomes, the odds of anxiety were statistically significantly lower for mefloquine users (OR = 0.6, 95%CI 0.43–0.83) than for those who did not use antimalarials. Phobia and panic attack both showed decreased odds for mefloquine users compared with nonusers, but the findings were not statistically significant. Psychosis was elevated for mefloquine users compared with nonusers, but the effect was not statistically significant. However, these analyses were based on any use of mefloquine, and the use was not stratified on current or past exposure time. This large, adequately powered study provides evidence of decreased odds of some neurologic and psychiatric adverse events in travelers prescribed mefloquine for malaria prophylaxis. However, the lower odds of anxiety and depression out- comes for mefloquine users versus the unexposed group suggests the possibility of uncontrolled confounding by contraindication. The comparison group con- sisted of travelers as well, but they may have traveled to non-malaria areas or had u ­ nmeasured risk factors that contraindicated antimalarial prophylaxis. The lower odds of adverse neurologic and psychiatric outcomes among mefloquine users in this study suggests that those prescribed mefloquine may have been screened more carefully for possible contraindications to mefloquine use. The 1-year medi- cal history used to assess psychiatric conditions is unlikely to reflect a complete psychiatric history. Overall, this was a well-designed study that found no increase in anxiety, stress-related disorders, or psychosis (combined outcome), depression, epilepsy, or peripheral neuropathy associated with mefloquine use for malaria prophylaxis in travelers aged ≥1 year when assessing current use and 18 months following current use. The odds of developing anxiety, stress-related disorders, or psychosis (combined outcome) and the odds of developing depression were statistically significantly lower in past users of mefloquine than in those who did not use an antimalarial and the odds were not statistically significantly different among current users, suggesting that these psychiatric outcomes resolve and do not persist. Using the same design and administrative database described by Schneider et al. (2013), Schneider et al. (2014) examined the incidence of clinical diagnoses of eye disorders (n = 652) in travelers aged ≥1 year with at least one prescription for mefloquine (n = 10,169), A/P (n = 28,502), or chloroquine and/or proguanil (n = 2,904) for malaria prophylaxis or no antimalarial prescription (but who had a pre- travel consultation) (n = 41,573) between January 1, 2001, and October 1, 2009. Individuals were excluded if they had a diagnosis of malaria prior to the start of antimalarial drug use; had cancer, alcoholism, or rheumatoid arthritis; or had been diagnosed with an eye disorder of interest (any eye disorder affecting the cornea,

MEFLOQUINE 125 lens, retina, uvea, iris, or other parts of the eye, or glaucoma). Because only 20 of the total 652 eye disorders occurred among people ≤17 years, although the number of users of each drug was not stratified by age, the committee presents the results as reported, and it does not believe that the interpretation of findings and infer- ences that can be made are overly influenced by the inclusion of people ≤17 years. Among mefloquine users, a total of 85 incident eye disorders were identified (23 within 90 days of finishing the prescription and 62 between 91 and 540 days of the end of the prescription). The eye disorders were grouped as disorders of the cornea, cataract, glaucoma, disorders of the retina, impairment in visual acuity, vitreous detachment, disorders of the uvea, or neuro-ophthalmologic disorders, with the latter including optic neuritis, diplopia, trigeminal neuralgia, and other conditions. Incidence rates were estimated for each eye disorder category by antimalarial group, but statistical comparisons between antimalarial user groups were not made. A nested case–control analysis was performed in which BMI and a history of depression, diabetes, hypertension, sleep disorders, and use of corticosteroids and contraceptives were controlled for. Compared with travelers who did not use any antimalarial drugs, the odds of developing any of the eye disorders of inter- est were elevated for mefloquine users combined (OR = 1.33, 95%CI 1.01–1.75). However, when mefloquine use was stratified by current (defined as use of drug plus 90 days post-cessation) and past use (91–540 days post-cessation) and com- pared with the nonusers, current users had nonstatistically significantly different odds (OR = 0.92, 95%CI 0.57–1.48) whereas past users had statistically signifi- cantly higher odds (OR = 1.56, 95%CI 1.14–2.14) of any of the eye disorders of interest, suggesting that the overall finding was driven by the association with past exposure. When each of the individual eye disorder categories was examined, only cataract was statistically significantly related to mefloquine use (both current and past use combined) (OR = 1.93, 95%CI 1.11–3.36). The strengths and limitations of this study mirror those discussed in Schneider et al. (2013) and Meier et al. (2004). Although “current use” likely captured some events within the 28-day post-cessation window, it was unlikely to result in selec- tion bias. The large study population allowed for adequate power to assess incident eye disorders as a whole as well as eight specific categories of disorders in travel- ers using mefloquine for malaria prophylaxis. The finding of an increased risk of cataracts with mefloquine use was unexpected and would require confirmatory evi- dence. Other risk factors for cataracts, such as occupation and sun exposure, were not included in the analysis and may have differed between the groups. Overall, the study suggests an increased risk of developing eye disorders in past users of mefloquine—and, for cataracts specifically, for any users of mefloquine—relative to nonusers of antimalarials. Schlagenhauf et al. (1996) conducted a prospective observational study of travelers to tropical Africa, all of whom had taken mefloquine for short-term malaria prophylaxis after visiting the Zurich University Vaccination Center between November 1992 and January 1994. The objective was to examine nonse-

126 LONG-TERM HEALTH EFFECTS OF ANTIMALARIAL DRUGS rious adverse events experienced during and following the use of mefloquine and to examine the association between adverse events and concentrations of racemic mefloquine, its enantiomers, and metabolite. Although study investigators did not make a traditional comparison between mefloquine exposed and unexposed groups, they did compare individuals who experienced adverse events with those who did not experience adverse events in the data analysis; thus, the committee included this study in their evaluation of the available scientific evidence. Of 420 recruited participants, complete data collection was available for 394 individuals. Participants were provided with mefloquine prophylaxis for the 2 weeks before travel, then during travel, and for 4 weeks after returning from their trips. Partici- pants were interviewed and had blood drawn after beginning mefloquine prophy- laxis but before travel and again after their return. As opposed to a list of symp- toms, adverse events were reported in response to the interview question “How do you feel since you took the last tablet?” Only adverse events with some impact on activities were included in the study. Adverse events were classified as “neuro- psychiatric” if they reflected sleep disturbances, dizziness/vertigo, headache, mood changes, unusual or vivid dreams, decreased concentration, or phobias. A total of 44 individuals experienced adverse events that affected activity, and 31 individuals (70.4% of those who experienced adverse events) experienced neuropsychiatric symptoms. Standardized instruments including computerized assessments of cognitive functioning (Neurobehavioral Evaluation System) and standardized self-report questionnaires assessing the severity of symptoms across body systems (Environmental Symptoms Questionnaire) and current mood state (Profile of Mood States) were administered to evaluate the neurologic and psychiatric adverse events. A subset of participants was assessed approximately 3 months after the last dose; it included only those participants who had experienced adverse events with some impact on activities along with a sex-, age-, and dosing-schedule-matched comparison group who had not experienced adverse events (controls). The results of the 3-month follow-up assessment are most relevant to the persistent effects of mefloquine since the other check points occurred while participants were still using the drug. Results from the Environmental Symptoms Questionnaire and the Profile of Mood States found greater though nonclinically significant symptoms of dizziness, light headedness, distress, restlessness, and sleep disturbance as well as more intense moods of tension, depression, fatigue, and confusion at baseline, but at follow-up there were no significant differences between controls and those who experienced adverse events. The majority of the adverse events were mild and transitory and did not result in statistically significant differences in performance on standardized neurobehavioral tests. When the plasma concentrations and ratios of the SR:RS enantiomers were analyzed, there was no statistically significant difference between participants with and without adverse events. Similarly, mean concentrations of mefloquine and its metabolite did not differ between mefloquine users who reported and who did not report adverse events. Overall, this study provides some information pertinent to the persistent neurologic and psychiatric

MEFLOQUINE 127 effects of mefloquine, suggesting that although there are some mild neurologic or psychiatric adverse events upon initiation of mefloquine, these symptoms tend to resolve by 3 months. The use of objective measures (blood draws) and stan- dardized, validated tests are strengths of the exposure and outcome assessment. Adherence was also specifically considered and found to be above 80% for all age groups. The study has several limitations, including that all study subjects received mefloquine so that the relationship of symptoms to the drug is unknown due to the lack of an unexposed comparison group, the fact that the comparison group at the start of the study was not followed for 3 months as was the subgroup who had experienced adverse events, and that the number people who reported adverse events (which were based on self-report) was small. Only adverse events with some impact on activities were included in the study. In addition, the groups of participants undergoing the standardized tests was both small in number and select (range 37% to 80% of those eligible). For the comparisons that were made, the matching was incomplete, making the control for covariates very limited. The authors postulated that the adverse events reported may have been the product of the stress of travel or even naturally occurring experiences. Schwartz and Regev-Yochay (1999) performed a prospective observational study, and followed 158 Israeli male and female travelers aged 22–65 years who took part in rafting trips on the Omo River, Ethiopia, and who had visited a travel clinic to obtain malaria prophylaxis. Travelers were prescribed mefloquine (250 mg once weekly), primaquine, doxycycline, or hydroxychloroquine by travel group. The primary aim of the study was to assess incident malaria and to compare the effectiveness of these four antimalarial drugs against both P. falciparum and P. vivax. Travelers were followed from the time of their return to Israel for an aver- age of 16.6 months (range 8–37 months) for incident malaria. Adherence to the prophylactic regimens and details about side effects were also collected by survey. The authors reported that “no severe side effects” were reported in any of the trav- elers and that no side effects or withdrawals were noted in the mefloquine users. The strengths of this study include its design and the long duration of follow-up (an average of 16.6 months after return from a malaria-endemic country). It is limited by its small sample size, nonrandomized design, and lack of details on adverse events beyond reporting that no severe events or withdrawals were reported among mefloquine users. As a result, this study provides limited information that can be used for inference. Research Volunteers DeSouza (1983) conducted a small clinical trial in a malaria-endemic area of Brazil. Healthy male volunteers were enrolled and administered a one-time dose of either 1,000 mg of mefloquine (n = 10) or 1,000 mg sulfadoxine and 50 mg pyrimethamine in a combined tablet (n = 10). Participants remained under sur- veillance in a hospital ward for the entire 66-day study period. A range of routine

128 LONG-TERM HEALTH EFFECTS OF ANTIMALARIAL DRUGS clinical assessments was conducted, including ECGs, measures of blood pressure and pulse rate, hematologic parameters and blood chemistry (red blood cell count, hemoglobin erythrocyte volume fraction, total and differential white blood cell counts, reticulocyte count, platelet count, cholesterol, triglycerides, glucose, urea, creatinine, etc.), and urine assays at varying intervals up to day 63 post-administra- tion. Adverse events of headache, diarrhea, and dizziness were reported following mefloquine administration, but all resolved by day 4. The authors reported that no significant changes were observed over the study period for blood pressure, pulse rate, ECGs, or any of the hematologic or biochemical parameters for either drug group. Prior to drug administration, 8 individuals in the mefloquine group had enlarged liver (versus 5 individuals in the sulfadoxine/pyrimethamine group), and 3 individuals in both the mefloquine and sulfadoxine/pyrimethamine groups had enlarged spleen, but the enlargements reduced over the course of follow-up. Spe- cific measures were grouped and reported as “day 14 onwards.” Notably, the dose of mefloquine administered was four times higher than that used for prophylaxis, and few adverse events were reported and none persisted beyond 4 days following administration. This study is limited by the very small study population and the inability to isolate health outcomes for the period 28 days following administra- tion of mefloquine. Laothavorn et al. (1992) conducted a prospective observational study of ECG changes in a Thai population of 102 patients with malaria and 18 healthy male volunteers receiving mefloquine. As treatment is outside the scope of this report, only the information regarding the healthy volunteers was considered. The healthy volunteers were administered 750 mg of mefloquine (three times higher than the dose used for prophylaxis). ECGs were performed prior to mefloquine adminis- tration, daily for 1 week following mefloquine administration, and then weekly up to day 42. No significant changes were found for biochemical, hematologic, or cardiac parameters, specifically heart rate, standard cardiac intervals, sinus arrhythmias, sinus bradycardia, ventricular ectopic beats, atrial ectopic beats, or atrial–­ entricular block at any time in the period following mefloquine administra- v tion. Given the small study size, the fact that the dose administered was three times higher than what is used for prophylaxis, the comparison of outcomes was with patients receiving treatment for malaria, and the inability to clearly isolate the time period of interest following cessation of drug exposure, this study provides limited evidence regarding persistent health effects from use of mefloquine. OTHER IDENTIFIED STUDIES OF MEFLOQUINE PROPHYLAXIS IN HUMAN POPULATIONS The committee reviewed several studies of mefloquine use in service mem- bers from the United States (Arthur et al., 1990; Boudreau et al., 1993; Nevin and L ­ eoutsakos, 2017; Sanchez et al., 1993; Saunders et al., 2015; Wallace, 1996),

MEFLOQUINE 129 A ­ ustralia (Kitchener et al., 2005; Rieckmann et al., 1993), France (Ollivier et al., 2004), Indonesia (Ohrt et al., 1997), Italy (Peragallo et al., 1999, 2001), the Netherlands (de Vries et al., 2000; Hopperus Buma et al., 1996), Sweden ­ (­ ndersson et al., 2008), Thailand (Eamsila et al., 1993), Turkey (Sonmez et al., A 2005), and the United Kingdom (Adshead, 2014; Croft et al., 1997; Terrell et al., 2015; Tuck and Williams, 2016). However, because the studies did not follow the military cohorts after mefloquine prophylaxis was complete or did not report on adverse events that occurred post-mefloquine-cessation (several studies followed the populations for cases of malaria only), these studies were not further considered. Several of the studies that did not meet inclusion were designed to examine the safety or tolerability of mefloquine when used for long-term (>4 months) pro- phylaxis in different populations, but they did not report on adverse events or other outcomes post-cessation. These studies examined populations of U.S. soldiers (Saunders et al., 2015), Dutch marines (Hopperus Buma et al., 1996; Jaspers et al., 1996; Todd et al., 1997), members of the Japanese Self-Defense Forces (Fujii et al., 2007), Thai soldiers (Eamsila et al., 1993), Turkish soldiers (Sonmez et al., 2005), U.S. Peace Corps volunteers (Korhonen et al., 2007; Landman et al., 2014; Lobel et al., 1991, 1993), harbor workers in Columbia (Rombo et al., 1993), Chinese railway workers in Nigeria (Olanrewaju and Lin, 2000), semi-immune populations (Sossouhounto et al., 1995), Thai gem miners (Boudreau et al., 1991), and British expats (Cunningham et al., 2014). Additionally, an integrated safety analysis of tafenoquine was conducted using five studies in which mefloquine was the com- parison in three of the studies, but the timing of adverse events (during use or post- cessation) was not reported (Novitt-Moreno et al., 2017). Nasveld et al. (2010) conducted a randomized double-blind controlled study to compare the safety and tolerability of tafenoquine with that of mefloquine (used for 26 weeks followed by primaquine for 2 weeks) for malaria prophylaxis in Australian soldiers; however, because the mefloquine comparison group also used primaquine, it was not con- sidered to contribute evidence of persistent effects of mefloquine alone. Studies of other populations were also excluded from the final set of studies evaluated in depth because the follow-up was not at least 28 days post-mefloquine- cessation or the follow-up was at least 28 days and adverse events were reported but the authors did not distinguish between the timing of those events (less than or at least 28 days post-cessation). Such studies included travelers from Australia (Phillips and Kass, 1996), Belgium (Peetermans and Van Wijngaerden, 2001), Denmark (Petersen et al., 2000), Finland (Vilkman et al., 2016), France (Carme et al., 1997), Germany (Huzly et al., 1996), Great Britain (Barrett et al., 1996; Bloechliger et al., 2014), Israel (Potasman et al., 2000, 2002; Schwartz et al., 2001), Italy (Laverone et al., 2006), Japan (Kato et al., 2013; Matsumura et al., 2005), the Netherlands (Hoebe et al., 1997; Sharafeldin et al., 2010; van Riemsdijk et al., 1997a, 2002a,b, 2004, 2005), and the United States (Hill, 2000; Kozarsky and Eaton, 1993; Lobel et al., 2001). Studies using combined populations of trav- elers who had visited clinics from several European countries, Canada, Israel, or

130 LONG-TERM HEALTH EFFECTS OF ANTIMALARIAL DRUGS South Africa (Durrheim et al., 1999; Lobel et al., 2001; Overbosch et al., 2001; Reisinger et al., 1989; Schlagenhauf et al., 2003, 2009; Steffen et al., 1990, 1993; Waner et al., 1999) were also reviewed but did not meet inclusion. An analy- sis based on the Hoffman-La Roche global drug safety database was excluded from final consideration because the timing of events could not be distinguished (­ damcova et al., 2015), as were six studies that used research volunteers to A examine the effects of mefloquine (Clyde et al., 1976; Davis et al., 1996; Hale et al., 2003; Hanboonkunupakarn et al., 2019; Rendi-Wagner et al., 2002; Vuurman et al., 1996). A small crossover study of Swissair trainee pilots was designed to determine the effects of steady-state mefloquine dosing on performance. Although participants who were first given mefloquine were followed for 4–6 months dur- ing the washout phase before being given a placebo, the authors did not report on adverse events that began or persisted during that time, and thus it was not further considered (Schlagenhauf et al., 1997). Upon full text review and quality assessment, additional studies were excluded from further consideration. Bijker et al. (2014) conducted a double- blind randomized controlled trial of experimental infection 16 weeks following the administration of prophylactic doses of mefloquine (n = 10) or chloroquine (n = 5) in healthy volunteers in the Netherlands. Adverse events and correspond- ing severity were recorded over the duration of the study; all adverse events were reported to have resolved by the end of the study, but because the exact timing of the resolution was not provided, this study was not included in the primary epide- miologic studies. Bunnag et al. (1992) conducted a randomized double-blind study comparing the efficacy and tolerability of Fansimef®, mefloquine, Fansidar®, and chloroquine to placebo for malaria prophylaxis in 602 healthy adult males in Thai- land who were followed for 4 weeks after the final dose. The timing of the adverse events was not specified, although blood measures were reported to remain stable throughout the study period, but because details were not presented the study did not meet inclusion criteria. Similar to Bunnag et al. (1992), Salako et al. (1992) conducted a randomized double-blind trial to assess the efficacy of Fansimef®, mefloquine, Fansidar®, and chloroquine compared with a placebo in semi-immune individuals. The follow-up extended for 4 weeks following the cessation of pro- phylaxis, but neither the details of what data were collected during those 4 weeks nor the timing of the adverse events were provided, and thus this study did not meet the criteria for inclusion as a primary epidemiologic study. In an early field trial conducted in 1977 to test the efficacy of three different doses and regimens of mefloquine against two regimens of sulfadoxine-pyrimethamine and a placebo, a semi-immune Thai population was administered the drug regimens for 26 weeks, with follow-up assessments conducted monthly for 3 months after the final dose. The authors stated that there was “no clinical evidence of drug toxicity” in any of the 990 participants and that no significant changes were found in the measured biochemical parameters, but no additional details of adverse events were reported in general or by regimen (Pearlman et al., 1980).

MEFLOQUINE 131 Case Reports and Case Series Published case reports can offer detailed information about symptoms and their course, such as the timing of onset in relation to exposure to the drug, treat- ment, remission, and persistence of symptoms, but they rarely generate informa- tion for causative inference. To be considered, published case reports and case series had to report on a follow-up of at least 28 days post-mefloquine-cessation. Of the 56 case reports identified, many reported only acute symptoms that resolved within 28 days post-cessation. The committee closely reviewed the remaining 20 case reports (totaling 25 patients) that had been identified (Baker, 1996; Borruat et al., 2001; Chester and Sandroni, 2011; Dietz and Frolich, 2002; Eaton, 1996; Even et al., 2001; Jain et al., 2016; Javorsky et al., 2001; Jha et al., 2006; Katsenos et al., 2007; Lobel et al., 1998; McEvoy et al., 2015; Meszaros and Kasper, 1996; Nevin, 2012; Potasman and Seligmann, 1998; Tran et al., 2006; Udry et al., 2001; Walker and Colleaux, 2007; Watt-Smith et al., 2001; Whitworth and ­ ichhorn, A 2005) as well as eight case series papers (Adamcova et al., 2015; Bem et al., 1992; Beny et al., 2001; Croft and Garner, 2000; Croft and Herxheimer, 2002; Ringqvist et al., 2015; Smith et al., 1999; van Riemsdijk et al., 1997b). Among the case reports, all patients had acute effects, and 16 patients had persistent neurologic or psychiatric effects for more than 28 days following their last dose of mefloquine. These symptoms included dizziness, anxiety, depression, insomnia/exhaustion, paranoia, hallucinations, visual illusions, mania, depersonalization, and suicidal ideation. Nevin (2012) published a detailed case of a patient who took mefloquine and acutely experienced anxiety, then developed fatigue, confusion, psychosis, dissociation, personality change, tinnitus, vertigo, dizziness, disequilibrium, and cognitive deficits, and he exhibited parasuicidal behavior. Objective testing discovered central ­ estibulopathy. The resultant diagnoses included vertigo of v central origin, toxic encephalopathy, various psychiatric disorders, ataxic gait, and memory loss. Persistent findings (follow-up ended after 10 months of first symptom onset) following the resolution of symptoms of psychosis, were fatigue, vertigo, disequilibrium, visual illusions, photosensitivity, memory impairment, and personality changes. One case of persistent retinopathy (Walker and Colleaux, 2007) and other ocular disturbances (Jain et al., 2016), one case of tinnitus resulting in hearing loss (Lobel et al., 1998), and one case of worsening psoriasis (Potasman and ­ eligmann, 1998) following mefloquine administration were reported. Addi- S tional cases reported neuropathy (Chester and Sandroni, 2011; Jha et al., 2006; Watt-Smith et al., 2001); paralysis, trouble breathing, heart palpitations (Eaton, 1996); eosinophilic pneumonia (­ atsenos et al., 2007); weakness (Jha et al., 2006; K W ­ hitworth and Aichhorn, 2005); skin rash (Eaton, 1996; Jha et al., 2006); and pain in the face and extremities (Chester and Sandroni, 2011). Five case series reported similar symptoms to those in the individual case reports. Beny et al. (2001) reported on 15 travelers who prematurely terminated

132 LONG-TERM HEALTH EFFECTS OF ANTIMALARIAL DRUGS their travel because of neurologic or psychiatric symptoms, and 7 of those had taken mefloquine. Of the mefloquine users, three had persistent anxiety and depression, although the timing of these symptoms relative to mefloquine use was unclear. In a review of adverse events reports submitted to the drug manufacturer, Bem et al. (1992) found 430 cases of adverse events when mefloquine was used prophylactically. More than half (56%) of these events were considered neuro- logic or psychiatric, as defined by WHO, and 59 of these individuals required hos- pitalization or resulted in severe disability. There were 26 reported cases of con- vulsions, and half of these cases had a neurologic or psychiatric history. All but one of the cases of convulsions resolved within 1 month of the last dose of meflo- quine. Additionally, Bem reported 12 cases of depression or “manic-­ epression,” d and 9 of those cases had suicidal ideation or attempts, or both. Psychosis was ­ reported in 20 cases, and 11 of those individuals recovered within 40 days (mean 21 days), while 2 recovered within 4–7 months. There was one case of toxic encephalopathy reported, but that person recovered within 3 months. Using post- marketing surveillance data of mefloquine in the Netherlands, van ­ iemsdijk et R al. (1997b) reported on 132 cases with a range of symptoms including depression, anxiety, agitation, nightmares, insomnia, concentration impairment, ­ sychosis, p hallucinations, depersonalization, and paranoia. Of the 132 cases, 36 had persis- tent symptoms, 74 had complete recoveries following cessation of mefloquine, and the disposition of the remaining 22 people was unknown. Using reports of adverse events to the manufacturer’s drug safety database between February 1984 and January 2011, Adamcova et al. (2015) performed an analysis of eye disorders associated with the prophylactic use of mefloquine. A total of 591 individuals were identified who experienced 695 eye disorder events, 223 of which were con- sidered serious, that were subsequently categorized into visual acuity (to include blindness, reduced visual acuity, visual impairment, and blurred vison), events affecting the anatomical parts of the eye (retina, vitreous, lens, cornea, optic nerve and glaucoma, and other disorders), and neuro-ophthalmic disorders. The temporal relationship of mefloquine use to adverse events was considered. When available, risk factors such as relevant medical history, comedication, and associ- ated conditions were also considered. The time of onset, which was available for only 70 of the events, ranged from 1 hour to 1,095 days (median 16.5 days). The duration of adverse events was known for only 5% of reports and, among those, ranged from 30 minutes to 270 days (median 10.5 days). Symptoms of optic neuropathy were reported for 48 individuals (53 events); 8 individuals (reporting 10 events) recovered, with sequelae that continued to affect visual acuity; and 3 individuals reported no complete recovery. Six events involving the cornea and five events involving the lens were reported, but eight of these had explanations other than mefloquine exposure and three of the reports did not contain sufficient information for a medical assessment. Of the 23 events involving retinal disor- ders, 9 were maculopathy, and most of these events were considered to be due to factors other than mefloquine.

MEFLOQUINE 133 Ringqvist et al. (2015) reported on 73 adults with mefloquine-associated adverse events (67 of them had used mefloquine for malaria prophylaxis) based on 95 reports to the Danish National Drug Authority Committee of Adverse Drug Reactions. Each person was contacted, and standardized instruments or interviews were used to elicit and categorize symptoms; these measures were completed 270–2,010 days following the adverse event. For 77% of cases, the individuals reported their symptoms as beginning in the first 3 weeks of mefloquine use, while 15% reported an onset of symptoms after 1–2 months of use, and 8% reported a symptom onset more than 8 weeks after the initiation of mefloquine. Of the 73 people, 45 reported physical symptoms, 27 reported signs of anxiety, 26 reported sleep disturbances including nightmares, 18 reported depression or feeling low, 11 reported signs of possible psychotic states (delusions/hallucinations), 9 reported cognitive problems, 3 reported confusion, and 1 reported mania; 40 individuals reported more than one complaint. Perceptual disturbances/hallucinations or delu- sional experiences were reported by 17 individuals following mefloquine use; all of these resolved within 9 months, and most within 3 weeks. Recurring nightmares were reported for 43 cases, and 9 individuals continued to have recurring night- mares for more than 3 years after mefloquine cessation. Cognitive dysfunction was reported in 42 cases and persisted for more than 3 years for 14 people. Included individuals reported significantly worse psychiatric symptoms than the matched controls in the Danish normative sample. Of the participants, 41% reported that they had obtained some treatment for their psychiatric adverse event. Although this case series provides some evidence supporting the development of persistent psy- chiatric problems after mefloquine use, the series was limited in that it was based on 73 cases of adverse events deemed severe enough to be reported to the Danish national registry. It is not known how complete the reporting to the Danish registry is, and there was no appropriate comparison group, only a comparison to Danish national norms for the self-report questionnaires administered after cases were reported to the registry. The investigators estimated that adverse events occurred at a rate of about 2 per 10,000 doses, suggesting that serious persistent events, if related to mefloquine, are rare. A Cochrane review by Croft and Garner (2000) identified 136 published case studies totaling 516 nonimmune travelers who had experienced adverse events while using mefloquine. Of those 516 individuals, 328 were using mefloquine as malaria prophylaxis. Four case reports involved fatal reactions to mefloquine, but it is unclear whether the deaths were reported in cases involving mefloquine pro- phylaxis or treatment, and further details were not provided. The authors discussed the best measures of tolerability and the possible influence of differences among groups (e.g., gender, weight, age, ethnicity) on the occurrence of adverse events, but they did not provide analyses or conclusions regarding the case reports. It was not clear how many of these people had persistent symptoms, and, other than a listing of the citations, additional information was sparse. Croft and Herxheimer (2002) elaborated on these 516 cases, reporting that 328 of the individuals had taken

134 LONG-TERM HEALTH EFFECTS OF ANTIMALARIAL DRUGS mefloquine prophylactically, and the median duration of adverse events symptoms was 16 days (range 1–550). The authors postulated that the symptoms associated with taking mefloquine were primarily related to liver or thyroid pathology. Smith et al. (1999) reviewed 74 published case reports of mefloquine use (prophylaxis or treatment) specific to dermatologic adverse events. Some of these cases were collected from outcomes of clinical trials, and nearly half had used mefloquine as treatment for malaria. The onset of the dermatologic effects was recorded in only 11 of the cases. The most common symptoms were pruritus and itching, which were reported in more than 40% of the cases, followed by rashes. The majority of effects were reported as mild or moderate in intensity and were usually self-limiting, although the timing was not specified. Other dermatologic adverse events included two reports of cutaneous vasculitis and one report each of Stevens-Johnson syndrome and toxic epidermal necrolysis. Tickell-Painter et al. (2017b) performed a systematic review of reports of death or parasuicide (a suicide attempt not resulting in death) associated with meflo- quine when used at various dosages for malaria prophylaxis. The literature search included all forms of prospective and retrospective studies of individual case reports or reviews of case reports that reported deaths or parasuicide up to July 11, 2017. Each case was reviewed using a formal causality assessment based on a causality assessment by WHO’s Uppsala Monitoring Centre. When information was poor or conclusions could not be drawn, the event was categorized as “unclassifiable.” Of the 527 articles identified and reviewed, 17 reported deaths or parasuicide, and only 8 had sufficient detail to be included in a causality assessment. Two deaths were identified as having a probable association with mefloquine. Both were in children and were characterized as “idiosyncratic drug reactions” (one involved pulmonary fibrosis and interstitial pneumonia; the other involved erythema, blistering, other complications, and eventually cardiac asystole). In the first case, symptoms began during mefloquine use, and death occurred 5 weeks after drug cessation; in the second, symptoms began during mefloquine use, but it is unclear when or even if the mefloquine use was stopped. Eight deaths were deemed “unlikely” to have been related to mefloquine or “unclassifiable” because of insufficient information. The authors identified one parasuicide with a “possible” causal association. A 22-year- old woman experienced episodes of crying, emotional detachment, and low mood 1 day after taking mefloquine 250 mg; her symptoms decreased on days 5 and 6; after an additional dose 1 week later, she experienced a relapse of symptoms, with ideas of guilt and death, and feelings of body transformation; and 5 days later she was hospitalized after a suicide attempt by drowning. Authors noted that the origi- nal source provided no information regarding the individual’s past medical history, including her use of any other medications. The authors concluded that the number of deaths that could be reliably attributed to the prophylactic use of mefloquine is very low (Tickell-Painter et al., 2017b). In their discussion, however, the authors stated that a limiting factor in their review was poor reporting in the literature; few reports, including those

MEFLOQUINE 135 deriving from spontaneous adverse event reporting databases, provided sufficient detail to perform a critical assessment. Additionally, the cases represented different time points for the outcomes: some were concurrent and some were longer term, further limiting the contribution of this paper to this report. In summary, there are published cases of persistent neurologic, psychiatric, and other adverse events following exposure to mefloquine. The majority of these case reports and case series presented individuals whose symptoms eventually resolved, even if they initially persisted beyond 28 days following the last dose of the medication. Although the case reports are compelling, without larger samples or comparison groups to establish base rates of disorders, it is difficult to establish a causal role for mefloquine in these cases. Selected Subpopulations In the course of its review of the literature on mefloquine, the committee identified and reviewed available studies that reported results stratified by demographic, medical, or behavioral factors to assess whether the risk for adverse events when using mefloquine for prophylaxis is associated with being part of or affiliated with a specific group. This was not done exhaustively, and the evidence included in this section is generally limited to adverse events observed with concurrent use of mefloquine. Many of these studies did not meet the inclusion criteria of following their population for at least 28 days post-mefloquine- cessation, but the committee considers these findings to be important indicators when considering the evidence as a whole. The following risk groups were specifically considered: females in general and pregnant women in particular, people with low weight or BMI, people with allergies and chronic conditions who may be taking concurrent medications, and people who use alcohol, marijuana, or illicit drugs. Sex Differences When studies of the prophylactic use of mefloquine have reported results stratified by sex, several have shown that women are significantly more likely than men to experience adverse events with mefloquine. This was observed in studies that examined any adverse event (Phillips and Kass, 1996; van Riemsdijk et al., 2002a) as well as for more specific outcomes including neurologic or psychiatric events (Huzly et al., 1996; Schlagenhauf et al., 1996, 2003; Schneider et al., 2013; van Riemsdijk et al., 1997a, 2002a, 2003, 2005) and gastrointestinal events (van Riemsdijk et al., 1997a) in several different types of populations and nationalities. In addition several studies found that women experience more severe adverse events that interfere with daily functioning than men (Rendi-Wagner et al., 2002; Schlagenhauf et al., 1996; Wernsdorfer et al., 2013), and that for women the time of onset of the adverse events is sooner and it takes longer for the symptoms to

136 LONG-TERM HEALTH EFFECTS OF ANTIMALARIAL DRUGS resolve (Rendi-Wagner et al., 2002; Wernsdorfer et al., 2013). Mefloquine is administered as a fixed-dose tablet of 250 mg salt in the United States or 228 mg base in other areas. While some studies that have measured serum levels of meflo- quine or its metabolites have found that mean levels are statistically significantly higher in women than men, sometimes nearly double (Potasman et al., 2002; Wernsdorfer et al., 2013), other studies did not find significant differences in serum levels between men and women (Schwartz et al., 2001). Possible explanations for sex-related differences may include reporting bias and greater adherence among women. Some of the observed differences between males and females might be due to females being more aware of neurologic and psychiatric disturbances than males and communicating symptoms more easily than males. For example, women report mental health problems at higher rates, particularly PTSD (Blanco et al., 2018; Breslau et al., 1997; Luxton et al., 2010; Norris et al., 2002) and depression (Breslau et al., 1995; Kessler et al., 1993; ­ uxton et al., 2010; Weissman and Klerman, 1977). However, several studies L have adequately controlled for these factors, and sex-related differences in adverse event reporting continue to be observed. It is also possible that biologic differences account for the heightened risk of PTSD and depression in women. These differences may include endocrine system differences, differences in neural connectivity in response to aversive stimuli, sex- by-genotype interactions, and sex differences in response to exposure to stress across the life span (see reviews by Eid et al., 2019, and Helpman et al., 2017). Sex differences of mefloquine distribution in cellular and fluid blood compartments, which may be related to the higher serum levels of mefloquine and its metabolites observed in women, may be associated with the occurrence of adverse events. However, Schwartz et al. (2001) found that although there was no difference in serum levels, women tended to be more susceptible than men to adverse events. Pregnancy In 2011 CDC recommended mefloquine for pregnant women both as a malaria treatment option and as an option to prevent malaria infection in all trimesters. For travel to areas where chloroquine resistance is present, mefloquine is the only medication recommended for malaria prophylaxis during pregnancy. Also in 2011, FDA reviewed available data for mefloquine use during pregnancy and reclassi- fied it from category C (animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite poten- tial risks) to category B (animal reproduction studies have failed to demonstrate a risk to the fetus and there are no adequate and well-controlled studies in pregnant women) (CDC, 2019). A 2018 Cochrane review concluded that mefloquine is safe in terms of adverse pregnancy outcomes, such as low birth weight, prematurity, stillbirths and abor-

MEFLOQUINE 137 tions, and congenital malformations (González et al., 2018). That Cochrane review considered data from six trials conducted between 1987 and 2013 in Benin, Gabon, Kenya, Mozambique, Tanzania, and Thailand and included 8,192 pregnant women who met their inclusion criteria (Briand et al., 2009; Denoeud-Ndam et al., 2014; González et al., 2014a,b; Nosten et al., 1994). Initial concerns regarding the pos- sible association between mefloquine and stillbirth were raised in a retrospective analysis in Thailand (Nosten et al., 1999) and a study of U.S. Army service women (Smoak et al., 1997) in which high rates of abortions were reported with meflo- quine exposure in pregnancy. Smoak et al. posited that exposure to other stress factors could have increased the rate of abortions in the Army service women. These concerns about adverse reproductive outcomes have not been supported by studies of malaria prevention during pregnancy conducted in sub-Saharan Africa or Thailand (Briand et al., 2009; González et al., 2014b; Nosten et al., 1994; Schlagenhauf et al., 2012; Steketee et al., 1996). A postmarketing study of 1,627 spontaneous reports of women exposed to mefloquine before or during pregnancy estimated the birth prevalence of congenital malformations in women exposed to mefloquine to be 4%—no different from the prevalence observed in the general population (Vanhauwere et al., 1998). Mefloquine is not as well tolerated as other antimalarial drugs when used for intermittent preventive treatment in pregnancy (IPTp), but the dosage used is substantially higher than the dosage used for malaria prophylaxis. The 2018 Cochrane review reported that when it was used for IPTp, mefloquine was associated with higher risks of drug-related vomiting (RR = 4.76, 95%CI 4.13–5.49; 6,272 participants, 2 studies; high-certainty evidence) and dizziness (RR = 4.21, 95%CI 3.36–5.27; 6,272 participants, 2 studies; moderate- certainty evidence) in women without HIV. Briand et al. (2009) reported higher rates of vomiting, dizziness, tiredness, and nausea among mefloquine users for IPTp than among those using sulfadoxine-pyrimethamine (78% versus 32%), with all cases having resolved spontaneously within 3 days. They also reported that there were no neurologic symptoms reported among neonates born to women who had received mefloquine during pregnancy. Rupérez et al. (2016) evaluated the safety of IPTp with mefloquine compared with sulfadoxine-pyrimethamine for key infant health and developmental outcomes at 1, 9, and 12 months of age. No significant differences were observed in the psychomotor development milestones assessed. Among infants born to women in the mefloquine group, there was an increased risk of being unable to stand without help (RR = 1.07, 95%CI 1.00–1.14), walk without support (RR = 1.10, 95%CI 1.01–1.21), and bring solid food to the mouth (RR = 1.32, 95%CI 1.03–1.70) at 9 months of age as compared with the children born to women in the sulfadoxine-pyrimethamine group, but these differences were not found at 1 or 12 months. No other statistically significant differences were observed in any of the other developmental, nutritional, or morbidity items assessed in the study visits, leading the authors to postulate that the differences could be the result of chance due to multiple comparison testing rather than true differences.

138 LONG-TERM HEALTH EFFECTS OF ANTIMALARIAL DRUGS González et al. (2014b) reported no serious neurologic adverse events among the 4,749 pregnant women who were enrolled in an open-label randomized clinical trial conducted in Benin, Gabon, Mozambique, and Tanzania comparing mefloquine (n = 1,551 single dose, n = 1,562 split dose) with sulfadoxine-pyrimethamine (n = 1,561) for IPTp. They also found no difference in the prevalence of adverse pregnancy outcomes (including miscarriages, stillbirths, and congenital malformations) between groups. Low Body Mass Index Some studies of the prophylactic use of mefloquine have collected informa- tion on weight and BMI and have reported differences in the proportion or types of adverse events when results were stratified by these factors. For example, in a study of 169 French soldiers deployed to the Ivory Coast and randomly selected to take weekly mefloquine prophylaxis, those soldiers weighing the least (51–60 kg) reported the greatest number of adverse events (88.9% reported at least 1 adverse event, with a mean of 3.11 events per person) compared with the heaviest soldiers (81–115 kg; 52.9% reported at least one adverse event, with a mean of 0.94 events per person). Because mefloquine was administered as a fixed dose (the standard 250 mg pill), the concentrations of mefloquine as measured in urine were higher for lighter individuals (4.2–4.9 mg/kg among those weighing 51–60 kg versus 2.2– 3.1 mg/kg for those weighing 81–115 kg), and the soldiers who reported adverse effects weighed less than those without any symptoms (p < 0.03) (Ollivier et al., 2004). In a study of 73 men and 78 women who were given mefloquine 3 weeks before their intended travel to malaria-endemic areas, those with the lowest BMI (≤20 kg/m2) had the most impairment of mood state (particularly vigor and fatigue, measured using validated instruments) and a significantly increased reaction time; both effects were further modified by gender, with the most pronounced effects in women with the lowest BMI (van Riemsdijk et al., 2003). In a comparison of neurologic and psychiatric outcomes among mefloquine users (n = 58) and A/P users (n = 61) using the same validated tests as in van Riemsdijk et al. (2003), van Riemsdijk et al. (2002b) found that there were significant differences between people who took mefloquine and those who took A/P with respect to self-reported fatigue, vigor, and total mood disturbance, with those using mefloquine reporting worse scores. When stratified by BMI (≤25 versus >25 kg/m2), those taking meflo- quine reported worse psychiatric symptoms than those taking A/P in both strata. Some of the observations of people of lower weight or BMI having more adverse effects may be related to sex, as women are generally smaller and weigh less than men. However, in a study of nonimmune Danish travelers in which meflo- quine was compared with chloroquine and chloroquine plus proguanil, women reported depression more frequently than men (p = 0.005), but the frequency of adverse events was not associated with weight when stratified by gender (Huzly et al., 1996).

MEFLOQUINE 139 Chronic Health Conditions Travelers who have allergies or other chronic health conditions and do not have contraindications for mefloquine have been found to report larger numbers of adverse events and experience them more frequently than people without these conditions (Huzly et al., 1996). Moreover, people with chronic disease report psychiatric reactions significantly more often than those without disease. People who take other drugs concomitantly (such as to treat their chronic conditions) with prophylaxis have been found to report more adverse reactions (Huzly et al., 1996). Mefloquine elimination may be prolonged in those with impaired liver function, leading to higher plasma levels and a higher risk of adverse reactions. If the drug is administered for a prolonged period, periodic evaluations, including liver function tests and evaluations for “neuropsychiatric” effects, should be performed (FDA, 2016). Using an existing database of self-administered questionnaires collected from travelers returning to Europe from Eastern Africa (between July 1988 and December 1991) and again 3 months after travel, Handschin et al. (1997) analyzed the association of adverse events experienced by travelers using four different prophylactic drug regimens (mefloquine, chloroquine, chloroquine plus proguanil, and no antimalarial drug) with and without concurrent use of other medications. Individual symptoms and comedications were grouped into categories for analysis. A total of 78,614 travelers were included in the analysis, and the majority used mefloquine (n = 48,264), followed by chloroquine plus proguanil (n = 19,727), chloroquine alone (n = 6,752; 300 mg or 600 mg doses), and no prophylactic drug (n = 3,871). Responses from both questionnaires were combined, so that the timing or persistence of adverse events could not be distin- guished. Both the occurrence of adverse events (and the reported severity) and the use of any medications in addition to the antimalarials were self-reported. Among mefloquine users, 25,690 used a comedication, while 22,574 did not. Indi­ iduals v comedicating had 1.5 times the risk of adverse events of any type or severity compared with individuals using only mefloquine. For severe adverse events, the relative risk was 2.2 times higher for comedication than for mefloquine alone (p < 0.01). Similarly increased risks with comedication use were found for the other prophylaxis (and no use of prophylaxis) groups as well. The number and severity of adverse events among mefloquine users correlated with the number of comedications taken and were statistically different from those in individuals who did not use comedication (p < 0.01). Drugs used to treat neurologic or psychiatric conditions were associated with the highest increases in risk for adverse events and severity, but the risk of adverse events was also statistically significant for analgesics, anti-infectives, and antidiarrheals compared with no comedication. No increase in the rate of adverse events or severity was observed with cardiovascular drugs such as beta blockers.

140 LONG-TERM HEALTH EFFECTS OF ANTIMALARIAL DRUGS Concurrent Use of Alcohol, Marijuana, or Illicit Drugs A number of factors may place travelers at increased risk of experiencing adverse events while using mefloquine, including stressful events during travel, interruptions of sleep cycles, and the use of alcohol, marijuana, and, in some cases, illicit drugs. In a study of 1,340 Israeli travelers to the tropics, mefloquine was used by 70.7%, and 151 of them (11%) reported neurologic or psychiatric problems (Potasman et al., 2000). A follow-up questionnaire was sent to the 151 people who reported neurologic or psychiatric problems to ascertain the symptoms, severity, and use of illicit drugs (reported as yes or no). A total of 26 t ­ ravelers admitted to using recreational drugs during travel, but it is not known how many of these people also used mefloquine. In a case series of 15 Israeli travelers who had sought evaluation for psychiatric effects, 6 of them had used mefloquine for prophylaxis, and 8 had reported using marijuana, hashish, or c ­ haras; or LSD or Ecstasy (Beny et al., 2001). In three of these cases, the probable trigger of the psychiatric event was determined to be mefloquine or a combination of illicit drugs and mefloquine. Although consuming large quantities of alcohol concurrently with taking mefloquine prophylactically has been reported to increase adverse events in at least one case report (Wittes and Saginur, 1995), mixed results have been reported in larger studies. In a comparison of the neurologic and psychiatric adverse events among users of mefloquine (n = 394) and proguanil (n = 493) with people who did not take any prophylactic drug (n = 340), van Riemsdijk et al. (1997a) found that in regular users of alcohol, nightmares were more frequent among those who used mefloquine than among those that did not use antimalarials, but the authors also noted that the number of people who reported using alcohol in the meflo- quine group was statistically significantly higher than the group who did not use antimalarials (p = 0.01). To determine whether mefloquine affects psychomotor and actual driving performance when given at prophylactic levels, Vuurman et al. (1996) conducted a randomized double-blinded placebo-controlled study of 40 men and women. Alcohol was given to achieve a sustained blood-alcohol concen- tration of 0.35 mg/mL (for comparison, the legal driving limit in the United States in 0.8 mg/mL). The mefloquine group drove better than the placebo group with and without alcohol at all time points measured. At the low alcohol levels tested, mefloquine does not appear to potentiate adverse events of alcohol on driving per- formance and rather appears to have psychoactivating or provigilance properties rather than any that enhance maximum psychomotor ability. BIOLOGIC PLAUSIBILITY Weekly 250 mg oral doses of mefloquine used for prophylaxis result in plasma concentrations ranging from 0.25 to 1.7 µg/mL (0.66 to 4.5 µM) (Charles et al., 2007; Gimenez et al., 1994; Hellgren et al., 1990, 1997; Kollaritsch et al., 2000;

MEFLOQUINE 141 Looareesuwan et al., 1987; Mimica et al., 1983; Palmer et al., 1993; Pennie et al., 1993; Schlagenhauf et al., 1996). Given that 98% of a mefloquine dose is bound to plasma proteins, the free mefloquine concentration is ≤0.1 µM (Gribble et al., 2000). In two studies (Schlagenhauf et al., 1996; Schwartz et al., 2001), plasma levels of mefloquine did not correlate with adverse events, whereas in a more recent study (Tansley et al., 2010), plasma exposure of mefloquine as measured by Cmax and area under the curve, especially the latter, did correlate with adverse events. In this same study, the global safety profile of (+) mefloquine was no better than that of racemic mefloquine; these data (Tansley et al., 2010) did not support the hypothesis that (+) mefloquine may have lower central nervous system liabili- ties than the (–) mefloquine. As described in several reviews (Grabias and Kumar, 2016; McCarthy, 2015; Toovey, 2009), a number of mechanisms may be associated with concurrent adverse events observed in individuals using mefloquine for malaria prophylaxis. As a caveat, the committee does not discuss data from studies in which meflo- quine concentrations substantially exceeded the highest plasma levels (4.5 µM) observed in pharmacokinetic studies of mefloquine prophylaxis. With respect to central nervous system adverse events, limited animal data indicate a 4- to 13-fold accumulation of mefloquine in the brain and central nervous system (Barraud de Lagerie et al., 2004; Baudry et al., 1997; Caridha et al., 2008). In two human cell lines, mefloquine inhibited the membrane efflux protein P-glycoprotein, also known as multidrug resistance protein 1 (MDR1) (Pham et al., 2000; Senarathna et al., 2016). One study showed that MDR1 polymorphisms seem to be associ- ated with the “neuropsychiatric” adverse events of mefloquine during treatment, primarily in women (Aarnoudse et al., 2006). A 1983 report published by United Nations Development Programme, World Bank and WHO indicated that mefloquine did not exhibit mutagenic, teratologic, or carcinogenic effects in rats or mice (WHO, 1983). Dow et al. (2006) explored directed behavioral effects of mefloquine on behavior and neurotoxicity using a comprehensive dosing regimen and plasma mefloquine measures in rats. The results suggest that 187 mg/kg doses of mefloquine enhance activity profiles and cause mild neurodegeneration, as reflected in silver staining in rat gracile, ­ uneate, and solitary c tract nuclei. Behavioral and histologic abnormalities increased as doses exceeded the pharmacologic range. Of note, no pathologic changes were observed with lower “prophylactic” dosing (45 mg/kg), based on circulating mefloquine ­evels. l All testing was performed 24–48 hours after dosing, and thus persistent or latent effects were not examined. In vitro studies provide evidence for potential actions of mefloquine on neurons. Mefloquine inhibited the growth of two rat ­ euronal n cell lines with IC50 values ranging from 7 to 12 µM and produced changes in gene expression consistent with the hypothesis that the endoplasmic reticulum was the neuronal target (Dow et al., 2003, 2005). Similarly, mefloquine is neurotoxic at micromolar concentrations to cerebral cortical cultures from rat pups, possibly by an oxidative stress mechanism (Hood et al., 2010; Milatovic et al., 2011). However,

142 LONG-TERM HEALTH EFFECTS OF ANTIMALARIAL DRUGS it is difficult to extrapolate results from neuronal culture systems to in vivo action, owing to the inherent vulnerability of neurons lacking trophic support from other cell types normally present in nervous tissue (glia and extracellular matrix proteins). Other mechanisms could contribute to mefloquine effects on brain function. These include enhanced weak inhibition of acetylcholinesterase (McArdle et al., 2005; Zhou et al., 2006) and induction of autophagy (Shin et al., 2012). Mefloquine inhibits coupling of GABAergic neurons in the cortex and nucleus accumbens, regions that are important in affect and cognition (Allison et al., 2011; Heshmati et al., 2016). Mefloquine is a potent adenosine A2A receptor antagonist (Weiss et al., 2003), so that it modulates an array of downstream physiologic actions and could modulate sleep (Grabias and Kumar, 2016). Binding assays suggest that mefloquine has the capacity to bind to neurotrans- mitter receptors. Mefloquine is a partial 5-HT2A agonist with an EC50 value of 1.9 µM (Janowsky et al., 2014), and it is also a 5-HT3A and 5-HT3AB antagonist with respective IC50 values of 0.66 and 2.7 µM (Thompson and Lummis, 2008). Though the studies were not performed in neuronal cells, the results suggest that there is a potential for in vivo action on serotonin signaling under some conditions, which are associated with but not causally linked to psychiatric conditions, including depression, suicidality, and low mood. Mefloquine is an inhibitor of connexin 36 (Cx36) and connexin 50 (Cx50), which are gap junction proteins responsible for rapid, non-synaptic electrical c ­ oupling in neurons and other cells (enabling alterations of cellular excitation with- out actions at the membrane). Of particular relevance, Cx36 is present in the nervous system and has been implicated in numerous neuronal signaling processes, some of which are relevant to psychiatric or neurologic diseases (e.g., epilepsy, depression) (Cruikshank et al., 2004). The inhibition of the gap junction signaling has led to the use of mefloquine as a pharmacologic tool in studies exploring the biologic actions of gap junctions (Cruikshank et al., 2004). For example, mefloquine administration in rats can impair the processing of contextual fear, impairing retrieval and enhanc- ing extinction of freezing responses to the fearful context via inhibition of connexins (Bissiere et al., 2011), suggesting a role for connexins (and perhaps mefloquine) in the modulation of emotional memory processing. In one clinical trial, mefloquine led to mild hypoglycemia but did not alter calcium homeostasis (Davis et al., 1996). This mefloquine-induced hypoglycemia may result from the inhibition of potassium ion channels in pancreatic β-cells (Gribble et al., 2000), and it has the potential to affect metabolic function. Cx50 is highly expressed in the lens, and Cx50 knockout mice exhibit visual impairments and lens defects (Cruikshank et al., 2004), which may be of relevance to the visual deficits reported following mefloquine (Adamcova et al., 2015; Martinez-Wittinghan, 2006; Schneider et al., 2014). In addition, mefloquine is photoreactive (Aloisi et al., 2004; Motten et al., 1999) and may be involved in retinopathies associated with the accumulation of mefloquine in the retina (binding to melanin in retinal photoreceptors) (Nencini et al., 2008).

MEFLOQUINE 143 Mefloquine inhibits several cardiac potassium channels (El Harchi et al., 2010; Kang et al., 2001; López-Izquierdo et al., 2011; Perez-Cortes et al., 2015). In addition, Coker et al. (2000) argued that the negative inotropic action of meflo- quine is explained by the blockade of L-type calcium channels. In multiple cell types and in cardiac muscle, mefloquine perturbs calcium homeostasis, possibly by acting as an ionophore, similar to ionomycin (Adegunloye et al., 1993; ­ issinger B et al., 2015; Caridha et al., 2008; Coker et al., 2000; Unekwe et al., 2007). Caridha et al. (2008) argue that mefloquine has the requisite physicochemical properties of an ionophore, given its high affinity for membrane phospholipids (Chevli and Fitch, 1982; Go and Ngiam, 1997). Mefloquine also was found to inhibit s ­ arcoendoplasmic reticulum calcium adenosine triphosphatase (SERCA) (Toovey et al., 2008) and calcium-activated chloride currents in a whole-cell patch clamp study (Maertens et al., 2000). The modulation of potassium and calcium signaling may be associated with but not causally linked to long-term actions of mefloquine on the heart. Overall, these data suggest multiple mechanisms that could account for the adverse events associated with concurrent mefloquine use. However, these data do not definitively link mefloquine to adverse events in the context of the repeated dosing that occurs during prophylaxis. All of these studies have measured end- points immediately after mefloquine administration, making it difficult to assess or infer potential lasting or permanent pathologic changes. SYNTHESIS AND CONCLUSIONS In assessing all of the available, relevant evidence, the committee was struck by the few number of studies available that examined outcomes that occurred after or persisted for more than 28 days after use of mefloquine had ceased. Of the 11 epidemiologic studies that met the ≥28-day post-cessation criterion for inclusion, the methodologic quality of the studies varied greatly, as did the time periods in relation to cessation and when studies were published (1983 through 2018) and the range of adverse events and health outcomes that were considered or reported. For example, although seven studies collected and reported information that could be categorized as psychiatric outcomes, these ranged from nonspecific broad catego- ries such as “neuropsychiatric” to specific symptoms, such as sleep disturbances or anxiety, or clinical diagnoses such as PTSD, depressive disorder, or psychosis, which made it difficult for the committee to make an integrated assessment. Given the inherently imperfect information generated by any one study, it would be desirable to have similar studies to assess consistency of findings, but the diversity of the methods makes it very difficult to combine information across the studies with confidence. Even when pertinent data appear to have been collected to meet the committee’s inclusion criteria of reporting on an adverse event or health out- come (or if there were none reported) 28 days post-drug-cessation, not all of the

144 LONG-TERM HEALTH EFFECTS OF ANTIMALARIAL DRUGS information relevant to the committee’s charge was presented because it was not a main objective or focus of the study (e.g., studies that were designed to exam- ine long-term efficacy against clinical malaria). Only published information that was presented from the study was considered. In some cases, it was clear that the investigators collected more data than was reported, such as when the population was followed for months or even years after mefloquine cessation, but the only outcomes reported were incident cases of malaria or generic statements about all adverse events having resolved. Given the diversity of the methodologic quality and the variety of outcomes examined, the summarized epidemiologic studies did not all contribute equally to the ultimate conclusion of the association between mefloquine and persistent events of a given health outcome, and, in particular, the inferences are based primarily on those few studies that had the following attributes: • sound designs and analysis methods; • documented exposure of mefloquine for malaria prophylaxis; • documented health outcomes at least 28 days after cessation of mefloquine use; • compared mefloquine users with similar people who did not use any antimalarial drug, were given a placebo, or who used other antimalarial drugs; • large enough sample sizes to conduct informative analyses; and • presented empirical information relevant to associations between adverse effects or events (or lack of any effects or events) ≥28 days after meflo- quine use had ended. In general, the post-cessation epidemiologic studies were not designed to examine the persistence of events in individuals, but rather they collected informa- tion on whether adverse events were detected at some time period at least 28 days after cessation of mefloquine. To avoid repetition for each outcome category, a short summary of the attributes of each study that were considered to be most contributory to the evidence base or that presented evidence germane to multiple body system categories is presented first. The evidence summaries for each out- come category refer back to these short assessment summaries. For each body system category, supporting information from the FDA label and package insert, known concurrent adverse events, case studies, information on selected subpopulations, experimental animal and in vitro studies, and results from epidemiologic studies that were less methodologically sound is first sum- marized before the evidence from the assessed epidemiologic studies is presented. While the charge to the committee was to address persistent or latent adverse events, the occurrence of concurrent adverse events enhances the plausibility that problems may persist beyond the period after cessation of drug use. The synthesis of evidence is followed by a conclusion about the strength of evidence regarding

MEFLOQUINE 145 an association between the use of mefloquine and persistent adverse events and whether the available evidence would support additional research into outcomes of that body system. The outcomes are presented in the following order: neuro- logic disorders, psychiatric disorders, gastrointestinal disorders, eye disorders, cardiovascular disorders, and other outcomes including dermatologic outcomes and disorders of other organ systems. Epidemiologic Studies Presenting Contributory Evidence Eick-Cost used DoD administrative databases to perform a large retrospec- tive cohort study among active-duty service members who filled at least one prescription for mefloquine, doxycycline, or A/P between 2008 and 2013. The primary study objective was to assess and compare the risk of incident and recur- rent ICD-9-CM-coded neurologic and psychiatric outcomes that were reported at medical care visits during concurrent antimalarial use plus 365 days after the end of a prescription. This was a well-designed study and included several important factors that increased its methodologic quality: a large sample size, an adminis- trative data source for both exposure and outcomes, and careful consideration of potential confounders including demographics, psychiatric history, and the mili- tary characteristics of deployment and combat exposure. Because the neurologic and ­ sychiatric diagnoses occurring during current and recent use were analyzed p together without distinguishing between events that occurred within 28 days of antimalarial use and those that occurred ≥28 days post-cessation, it provides no quantitative information regarding the persistence of most events other than the notation in the text that the results did not change when restricted to a post- cessation period of 30 days. Whereas the use of medical diagnoses is likely to be more reliable for the outcomes than self-report, there was no validation of the diagnoses recorded in the administrative databases, and symptoms or events that did not result in a medical visit or diagnosis would have been missed. For PTSD diagnoses, there was no information concerning when the index trauma occurred. Schneiderman et al. (2018) conducted an analysis of self-reported health outcomes associated with the use of antimalarials in a population-based cohort of deployed and nondeployed U.S. veterans, using information collected as part of the NewGen Study. Exposure and outcomes were systematically obtained, and psy- chiatric outcomes were measured by standardized assessment instruments. Anti- malarial medication use was grouped by mefloquine, chloroquine, ­ oxycycline, d primaquine, mefloquine in combination with other drugs, other antimalarials, and not specified or no antimalarial drug exposures. Health outcomes were self- reported using standardized instruments: the SF-12 for general physical health status, PCL-C for PTSD, and the Patient Health Questionnaire. The overall sample was large, and the researchers used a reasonably thorough set of ­ ovariates in c models estimating drug–outcome associations, including deployment and combat exposure. Although the time period of drug use and the timing of health outcomes

146 LONG-TERM HEALTH EFFECTS OF ANTIMALARIAL DRUGS were not directly addressed, given that the population consisted of veterans who had served between 2001 and 2008 and the survey was not administered until 2009–2011, it is reasonable to assume that antimalarial drug use had ceased some time before. The methodology and response rate (34% total; weighted 4.4% of deployed and weighted 2.2% of nondeployed individuals used mefloquine) for this study may have led to the introduction of non-response, recall, or selection biases; however, the committee believed that investigators used appropriate data analysis techniques to mitigate the effects of any biases that were present. Wells et al. (2006) was a large, well-designed study that used DoD admin- istrative databases to examine incident hospitalizations by body system among active-duty service members who had been prescribed mefloquine and deployed at some time in calendar year 2002. Because the follow-up of mefloquine users began at the time of their return from deployment, it is reasonable to assume that these results largely reflect experience following the cessation of exposures of varying duration. Nonetheless, the results for varying time intervals following the cessation of use (or time since return from deployment) were not presented. Two comparison groups who were not prescribed antimalarials (service mem- bers assigned to Europe or Japan and service members who were deployed for 1 month or longer) were used in the analysis, but the demographic and military characteristics of the Europe- or Japan-assigned individuals differed substantially from those of the deployed individuals, suggesting that this was not an appropri- ate comparison group. Several attributes of its design increase its methodologic quality: a large sample size, the use of an administrative data source for both exposure and ­ CD-9-CM-based outcomes, and the inclusion of a reasonable set I of sociodemographic, psychiatric history, and military characteristic covariates in the analyses. However, combat exposure was not specifically addressed, and although deployment may have been assumed to be a surrogate for combat, the lack of control for combat exposure itself is a limitation. The health outcomes were systematically and objectively ascertained but would reflect only the most severe experiences requiring hospitalization, which would likely exclude most people who experienced mental health symptoms or disorders. The small number of specific diagnoses for certain outcomes further limits the generalizability of these results. Three large, retrospective studies of travelers (Meier et al., 2004; Schneider et al., 2013, 2014) were conducted using data from the UK-based GPRD to assess the incidence and compare the odds of developing first-time neurologic, psychiatric, or eye disorders in individuals using mefloquine compared with other antimalarial drugs for malaria prophylaxis. While the specific outcomes examined differed by study, the general design and methodology were the same for all three. The use of GPRD data (a well-established platform designed for both clinical practice and research) allowed for adequate power to detect differences in outcomes and for a uniform collection of exposures (although recorded drug prescriptions do not equate to use or adherence) and outcomes (based on clinical diagnoses coded from

MEFLOQUINE 147 medical care visits) that were not subject to recall bias. Events that did not result in a medical care visit or that occurred outside of the national health care system would have been missed; however, it is unlikely that this would result in differ- ential selection bias. Diagnoses were defined a priori, which excluded other out- comes, including the potential to identify rare outcomes. The antimalarial-exposed populations were large, an appropriate comparison group of travelers not using any form of malaria prophylaxis was included, and health outcomes were reported in defined time periods, including current use through 90 days after a prescription ended (termed current use or recent use in analyses that included both irrelevant [7–27 days] and relevant [28–90 days] time periods) and 91–540 days following cessation of use (termed past use in analyses). Adjustments were made for several confounders, including age, sex, calendar time, practice, smoking status, and BMI using appropriate study design or analytic methods. Each study included a nested case–control component that allowed for control of important covariates. The primary aim of Tan et al. (2017) was to assess the prevalence of several health conditions experienced by returned Peace Corps volunteers associated with the use of prophylactic antimalarial drugs. The number of participants was large (8,931 participants), and of those who used an antimalarial drug a majority (59%) had used mefloquine. A number of important covariates, such as psychiatric history and alcohol use, were collected, but the study had several methodologic issues. These limitations included its study design (self-report Internet-based survey), exposure characterization based on self-report (which introduces several potential biases such as recall bias, sampling bias, and confounding), outcome assessment (based on self-report of health provider-diagnosed conditions up to 20 years post-service), the use of mixed comparison groups, a lack of detail regarding the analysis methods, and a poor response rate (11%, which likely introduced selection bias). The evidence generated by this study was thus considered to contribute only weakly to the inferences of mefloquine and persistent adverse events or disorders. Neurologic Disorders There are recognized concurrent adverse neurologic events associated with mefloquine use, including dizziness, vertigo, loss of balance, headache, memory impairment, confusion, encephalopathy, sensory or motor neuropathies, convul- sions, tinnitus, and hearing loss (FDA, 2016; Tickell-Painter et al., 2017a). In the epidemiologic studies examining persistent neurologic outcomes, these effects were not observed to occur at statistically different rates for mefloquine users compared with people who used other antimalarial drugs or who did not use any prophylaxis. However, persistent dizziness was found in a few case reports, and studies of mefloquine use in pregnant women showed an increased risk for dizzi- ness that resolved spontaneously within a few days (Briand et al., 2009; Nosten et al., 1994). A recent Cochrane review of mefloquine use for prophylaxis in travelers also reported that current mefloquine use was associated with statistically signifi-

148 LONG-TERM HEALTH EFFECTS OF ANTIMALARIAL DRUGS cantly higher risks of dizziness than placebo or no prophylaxis in cohort studies, but in clinical trials no difference in experiencing dizziness was found between mefloquine users and those given a placebo. Other persistent neurologic symptoms and conditions of neuropathy, weakness, paralysis, convulsions, and concentration impairment were described in the case reports. In addition to the data on neurologic outcomes in humans, animal and cell c ­ ulture studies lend some support for plausible biologic mechanisms through which mefloquine may contribute to neurotoxic processes. These include the mod- ulation of calcium homeostasis, the induction of oxidative stress, the inhibition of ­ onnexin signaling, and the modulation of neurotransmitter receptor binding. c The committee reviewed five epidemiologic studies that examined neurologic outcomes that occurred at least 28 days following the cessation of mefloquine (Eick-Cost et al., 2017; Schlagenhauf et al., 1996; Schneider et al., 2013; Tan et al., 2017; Wells et al., 2006). These outcomes were inconsistently identified and measured across studies: ICD-9-CM-coded disorders of the nervous system as a category, and specific neurologic outcomes of nystagmus, vertiginous syndromes, dizziness and giddiness, and migraine (Wells et al., 2006); ICD-9-CM-coded out- comes of confusion, tinnitus, vertigo, and convulsions (Eick-Cost et al., 2017); epilepsy and peripheral neuropathy (Schneider et al., 2013); “neuro­ sychologic” p as a category and that separately included dementia, migraines, seizures, ­innitus, t vestibular disorder, and “other” neurologic disorder (Tan et al., 2017); and “neuropsychiatric” adverse events that included dizziness/vertigo, headache, and decreased concentration (Schlagenhauf et al., 1996). While all five of these studies have methodologic limitations, the three that provided the most evidence for potential persistent or latent neurologic outcomes based on the strength of the methods used were Eick-Cost et al. (2017), Wells et al. (2006), and Schneider et al. (2013). In their analysis of data from DoD administrative databases, Eick-Cost et al. (2017) examined neurologic outcomes, and analyses were stratified by deploy- ment and, separately, by psychiatric history. Adjusted incident rates of tinnitus, convulsions, and confusion were higher among the nondeployed than among the deployed groups who used mefloquine. There were no statistically significant differences for any of the neurologic outcomes among the deployed mefloquine users compared with the doxycycline users. Among the nondeployed, only ver- tigo was statistically significantly different (decreased) for mefloquine versus d ­ oxycycline users. Adjusted IRRs comparing mefloquine with A/P by deploy- ment status found that the risk of tinnitus was statistically significantly increased among both the deployed and the nondeployed groups. No other outcomes were statistically significantly different between deployed mefloquine and A/P users. For both the mefloquine and doxycycline groups, there were no statistically sig- nificant differences between drugs when adjusting for history of psychiatric dis-

MEFLOQUINE 149 order. In a second study of U.S. service members, Wells et al. (2006) presented hospitalizations from nervous system disorders as a single category. Only six hospitalizations due to nervous system disorders were reported for mefloquine users, and comparisons with both reference groups showed that mefloquine users had no statistically significant different risk for nervous system disorders as a group. When hospitalizations due to specific neurologic outcomes were consid- ered, among those receiving mefloquine there were no cases of nystagmus or dizziness and giddiness, one case of vertiginous syndromes, and three cases of migraine, which resulted in wide, imprecise, and null effect estimates when these rates were compared with those of the two reference groups of service members. Schneider et al. (2013) assessed incident diagnoses of epilepsy and peripheral neuropathy among trav­ lers who had been prescribed mefloquine and compared e them with those given another antimalarial and, separately, with travelers who had a travel consult but were not prescribed antimalarial drugs; the analysis was stratified by time since cessation. Over the approximately 8.5-year period of data examined, a total of 14 mefloquine users were diagnosed with incident epilepsy, 6 of whom were current use and 8 of whom were past use. Among the eight mefloquine users with incident ­ europathies, five were current users n and three were past users. In the nested case–control analysis, after adjusting for smoking and BMI, the odds of developing epilepsy were decreased, and the odds of developing peripheral neuropathies were elevated for mefloquine users, but neither of these results reached statistical significance. Similarly, when stratified by current use or past use, the adjusted odds of epilepsy for mefloquine users compared with non-antimalarial users were not statistically significantly different. The FDA package insert warns individuals with epilepsy that taking mefloquine may increase the risk for convulsions, and people who had previ- ously been diagnosed with epilepsy were excluded from the study. Compared with nonusers of antimalarials, current users of mefloquine had increased odds of neuropathy, while past users had decreased odds of neuropathy but neither of these estimates was statistically significant. In sum, this was a well-designed study, and the stratification of past use in particular provides some evidence for an absence of increased persistent neurologic effects of epilepsy and peripheral neuropathy following the use of mefloquine. Overall, these three well-designed studies provide some evidence for an absence of persistent neurologic events following the use of mefloquine, but the number of neurologic disorders was small, making these results far from definitive. The two other epidemiologic studies with post-cessation follow-up (­ chlagenhauf et al., 1996; Tan et al., 2017) that presented some information S on neurologic outcomes were not as methodologically robust as Eick-Cost et al. (2017), Wells et al. (2006), or Schneider et al. (2013), and their results lend additional weak support for an absence of increased persistent neurologic effects.

150 LONG-TERM HEALTH EFFECTS OF ANTIMALARIAL DRUGS Based on the available evidence, the committee concludes that there is i ­nsufficient or inadequate evidence of an association between the use of meflo- quine for malaria prophylaxis and persistent or latent neurologic events. Current evidence suggests further study of such an association is warranted, given the evidence regarding biologic plausibility, adverse events associated with concur- rent use, or data from the existing epidemiologic studies. Psychiatric Disorders The evidence supporting concurrent adverse psychiatric effects of mefloquine is compelling. These effects include anxiety, depression, mood swings, panic attacks, abnormal dreams, insomnia, hallucinations, aggression, and psychotic or paranoid reactions. Suicidal thoughts and death by suicide have been also been reported with concurrent use of mefloquine. While the charge to the committee was to address persistent or latent adverse events, the occurrence of concurrent adverse events enhances the plausibility that problems may persist beyond the period of drug use. The FDA package insert warns that psychiatric symptoms such as acute anxiety, depression, and restlessness should be viewed as potential precursors to more serious psychiatric or neurologic adverse events and that mefloquine should be discontinued if they occur. In addition, the FDA labeling has increasingly invoked the potential for persistent adverse psychiatric events, suggesting reports received warranted these changes, although no research is cited as the basis for these changes. Two Cochrane reviews examined concurrent adverse events of mefloquine use in travelers. Croft and Garner (2000) reported on psychiatric ­ ymptoms in six trials comparing the tolerability of mefloquine to s other antimalarials and found that the only outcomes with increased odds associ- ated with mefloquine use were insomnia and fatigue. Tickell-Painter et al. (2017a) found that mefloquine users were more likely than users of doxycycline and users of A/P to experience insomnia, anxiety, abnormal dreams, and depressed mood. In cohort studies mefloquine users were more likely than participants who did not take prophylaxis to experience abnormal dreams and insomnia. However, this review included concurrent adverse events, and several outcomes had imprecise effect estimates because of the small numbers of adverse events (e.g., serious adverse effects, depressed mood, abnormal thoughts or perceptions). Additional studies of selected sub­ opulations of concurrent mefloquine use lend some evi- p dence for a relationship with psychiatric outcomes. Mefloquine users who use another medication for a chronic illness (Handschin et al., 1997; Huzly et al., 1996) or who drink alcohol while taking mefloquine (van Riemsdijk et al., 1997a) appear to have an increased risk for adverse events. Furthermore, women (Rendi-Wagner et al., 2002; Schlagenhauf et al., 1996; Wernsdorfer et al., 2013) and individuals with low BMI (van Riemsdijk et al., 2002b, 2003) may be at increased risk for adverse psychiatric symptoms when taking mefloquine. A number of published case reports suggest that persistent psychiatric symptoms (including anxiety,

MEFLOQUINE 151 depression, insomnia/exhaustion, paranoia, hallucinations, visual illusions, mania, depersonalization, or suicidal ideation) may be associated with mefloquine use and continue beyond the period after drug exposure has ended. Again, these findings support the plausibility of persistent adverse events, but they are inherently lim- ited in the quality of scientific evidence that they can provide. However, a recent Cochrane review concluded that mefloquine is safe during pregnancy (González et al., 2018). Animal and in vitro studies indicate that mefloquine may negatively affect processes relevant to psychiatric conditions. Mefloquine can affect processes that may in turn interfere with brain circuits regulating mood and cognition, including calcium homestasis (synaptic signaling), oxidative stress (managing energetic challenge), and connexins (intercellular communication). In particular, mefloquine’s binding to serotonin receptors suggests possible interactions with signaling processes relevant to mood regulation. However, the data from these experimental studies do not definitively explore mefloquine exposures relevant to prophylaxis doses or use. Moreover, the studies have measured endpoints imme- diately after mefloquine administration, making it difficult to address persistent or latent pathologic changes. ­ The most weight for evidence of an association between use of mefloquine and persistent or latent psychiatric adverse events comes from the seven epide- miologic studies that examined psychiatric outcomes that occurred at least 28 days following cessation of mefloquine (Eick-Cost et al., 2017; Meier et al., 2004; Schlagenhauf et al., 1996; Schneider et al., 2013; Schneiderman et al., 2018; Tan et al., 2017; Wells et al., 2006). The seven studies each used different methods for measuring outcomes, and the psychiatric outcomes of interest varied across s ­ tudies. Considering the studies of U.S. military or veteran populations, Eick-Cost et al. (2017) examined adjustment disorder, anxiety disorder, depressive disorder, PTSD, psychoses, suicide ideation, paranoia, hallucinations, insomnia, and death by suicide using clinical diagnoses coded in DoD administrative databases. Wells et al. (2006) also used clinical diagnoses coded in DoD administrative databases to examine “mental disorders” as a diagnostic category and specific psychiatric diag- noses of somatoform disorder, mood disorder, anxiety disorder, PTSD, substance use disorders, personality disorder, adjustment reaction, “mixed syndromes,” and “other disorders.” And Schneiderman et al. (2018) used standardized self-report instruments to examine outcomes of PTSD, thoughts of death or self-harm, other anxiety disorders, and major depression. Both studies of UK travelers used clini- cal diagnoses coded in a health care administrative database to examine incident psychiatric outcomes. Meier et al. (2004) included depression, psychoses, panic attacks, and death by suicide among people aged 17–79 years, and Schneider et al. (2013) examined depression and anxiety, stress-related disorders, and psychoses as a group in individuals aged ≥1 year (Schneider et al., 2013). Schlagenhauf et al. (1996) used standardized self-report instruments to examine sleep disturbances, mood changes, unusual or vivid dreams, and phobias in travelers who had taken

152 LONG-TERM HEALTH EFFECTS OF ANTIMALARIAL DRUGS mefloquine for short-term malaria prophylaxis after visiting a Swiss vaccination center. In their analysis of returned U.S. Peace Corps volunteers, Tan et al. (2017) used unverified self-reported symptoms of depression, anxiety, and insomnia to derive clinical diagnoses of major depressive disorder, bipolar disorder, anxiety disorder, schizophrenia, obsessive-compulsive disorder, and “other.” Findings related to PTSD are considered separately, below. While all seven of these studies have methodologic limitations, the five that, based on their methodologic quality, provided the strongest evidence for examin- ing the presence of persistent psychiatric outcomes are Eick-Cost et al. (2017), Meier et al. (2004), Schneider et al. (2013), Schneiderman et al. (2018), and Wells et al. (2006). Four of the studies (Eick-Cost et al., 2017; Meier et al., 2004; S ­ chneider et al., 2013; Wells et al., 2006) evaluated data from administrative data- bases with clinically diagnosed outcomes, included at least two comparison groups in the analyses, applied a reasonably thorough set of covariates to the analyses of effect estimates, and measured the psychiatric outcomes of interest systematically and objectively, based on medical care visits and coded in the database. Although both Eick-Cost et al. and Wells et al. used data from DoD administrative databases, they used different years, and Wells et al. limited diagnoses to hospitalizations, which would suggest that the outcomes reported in Wells et al. were of greater severity than those in the Eick-Cost et al. sample, limiting the cross-study. The Schneiderman et al. (2018) study was somewhat less rigorous as the researchers based their exposure and outcome assessments on self-report. Both exposure and outcomes were systematically obtained, and psychiatric outcomes were measured by standardized psychometric instruments. The sample was large and adequately powered, and the investigators used a reasonably thorough set of covariates in analyses of effect estimates. Again, the difference in ascertainment of data limits comparison of data across studies. In their analysis of active-duty service members, Eick-Cost et al. (2017) found that with the exception of psychoses and death by suicide, the adjusted incident rates for psychiatric outcomes were higher among the deployed groups who used mefloquine than among the nondeployed groups who used mefloquine. When comparisons between mefloquine and doxycycline use were stratified by deployment, the only statistically significant difference for any of the psychiatric outcomes for the deployed was a slight increased risk for anxiety disorders among mefloquine users. Among the nondeployed, mefloquine users had statistically significantly decreased risks of adjustment disorder, insomnia, anxiety disorder, depressive disorder, and PTSD compared with doxycycline users, but no differ- ences were found for the other five psychiatric outcomes. In comparisons of meflo- quine users and A/P users by deployment status, no outcomes were statistically significantly different for the deployed, but in the nondeployed group, mefloquine users had an increased risk of PTSD, although no other psychiatric outcomes showed differences in risk between mefloquine and A/P users. For both the meflo-

MEFLOQUINE 153 quine and doxycycline groups, individuals with a psychiatric diagnosis in the year preceding the prescription had statistically significantly elevated risks for a subsequent diagnosis of the same condition for all conditions reported (adjustment disorder, anxiety, insomnia, depressive disorder, and PTSD) compared with indi- viduals without a diagnosis in the prior year. However, when the IRRs comparing mefloquine and doxycycline users were stratified by those with and without prior psychiatric diagnoses, there were no statistically significant differences between mefloquine and doxycycline for any of the conditions. The results of a sensitiv- ity analysis in which the risk period was restricted to 30 days post-prescription were not reported, although the authors stated that the results were similar to the primary analyses. Similarly, in their analysis of service member hospitalizations Wells et al. (2006) reported a total of 37 hospitalizations for mental disorders as a category for mefloquine users, and the rate of hospitalizations was not statistically significantly different from the two comparison groups. When hospitalizations due to specific psychiatric outcomes were considered, there were no cases of somato- form disorders, 6 cases each of mood disorders and anxiety disorders, 1 case of PTSD, 19 cases of substance use disorders, 7 cases of personality disorders, 13 cases of adjustment reactions, 4 cases of mixed syndromes, and 20 cases of “other disorders” among mefloquine users, which resulted in imprecise and null effect estimates when these rates were compared with those of the two reference groups of service members. Using a large population-based cohort of deployed and non- deployed U.S. veterans, Schneiderman et al. (2018) found that, like Eick-Cost et al., deployed mefloquine users had higher frequencies of mental health diagnoses than nondeployed mefloquine users for the four psychiatric outcomes examined. However, in the adjusted logistic regression models with all covariates considered (including demographics, deployment, and combat exposure), mefloquine was not associated with any of the psychiatric outcomes examined: composite mental health score, thoughts of death or self-harm, other anxiety, and major depression. It is noteworthy that adjusting for combat exposure consistently reduced the mea- sures of association, but when combat exposure intensity was specifically consid- ered, the weighted prevalence estimates indicated that the prevalence of disorders increased with greater combat exposure intensity. This study could not address explicitly the health experiences during use and in specific time intervals following the cessation of use. Overall, the studies in military service members and veterans were well designed and provide some evidence for an absence of increased risk of persistent or latent psychiatric outcomes in mefloquine users. Factors that may be present in groups of military or veterans that may con- found associations between the use of mefloquine and adverse psychiatric events, such as deployment and combat exposure, are rarely encountered with leisure ­ravelers. The results of Meier et al. (2004) and Schneider et al. (2013), who used t UK travelers and stratified by time post-cessation corroborated the findings of Eick-Cost et al. (2017) and Schneiderman et al. (2018) in that the use of meflo- quine was not associated with an increased risk of depression diagnoses in either

154 LONG-TERM HEALTH EFFECTS OF ANTIMALARIAL DRUGS the cohort analysis or the nested case–control studies. Schneider et al. (2013) found that in the adjusted analyses, the odds of developing an incident diagnosis of depression was statistically significantly decreased in both current and past mefloquine users compared with nonusers. Meier et al. (2004) also found no dif- ference in the risk of developing depression for recent mefloquine users versus all past users of other antimalarials. Schneider et al. (2013) found that when the data were stratified by current use or past use, the adjusted odds of anxiety, stress- related disorders, or psychosis as a group were no different in current users but were statistically significantly reduced in the past users of mefloquine compared with nonusers. When anxiety, psychosis, phobia, and panic attack were analyzed as separate outcomes with no timing stratifications, compared with nonusers of antimalarials, only the odds of anxiety were statistically significantly decreased for mefloquine users (which was consistent with the findings of Eick-Cost et al.). Meier et al. (2004) found that first-time diagnoses of panic attacks and ­ sychosis p were not statistically significantly different for recent users of mefloquine com- pared with all past users of antimalarials, but the odds of panic attacks were statistically significantly increased in the adjusted nested case–control analysis. Both Meier et al. and Schneider et al. excluded people who had previously been diagnosed with the psychiatric outcomes of interest from their study populations. In sum, the studies of travelers corroborate the findings of studies of service mem- bers and veterans, and the use of stratification of post-cessation time, particularly past use, provides some evidence for an absence in—and possibly even a reduction in—persistent psychiatric effects of anxiety, stress-related disorders, or psychoses as a group, depression, and panic disorder following the use of mefloquine, but the small number of incident diagnoses for these psychiatric disorders does not provide definitive evidence of no effect. The two other studies considered by the committee that presented some information on psychiatric outcomes (Schlagenhauf et al., 1996; Tan et al., 2017) were not as methodologically robust as Eick-Cost et al. (2017), Wells et al. (2006), Schneider et al. (2013), Meier et al. (2004), or Schneiderman et al. (2018), and therefore their findings were given less weight. However, the results of these two studies overall lend additional weak support for an absence of persistent or latent psychiatric events. PTSD Three studies—all conducted using active-duty U.S. military or veteran populations—reported PTSD diagnoses (based on ICD-9-CM codes) or PTSD symptoms (based on validated instruments). Each of these studies adjusted for deployment and combat in the analysis of PTSD and other psychiatric outcomes. Adjusted effect estimates showed attenuated associations between mefloquine exposure and diagnoses or symptoms of PTSD. In an analysis of active-duty service members, Eick-Cost et al. (2017) presented adjusted effect estimates of

MEFLOQUINE 155 PTSD stratified by deployment status. Among the nondeployed, those who were prescribed mefloquine were found to have a statistically significant decrease in PTSD diagnoses relative to those prescribed doxycycline, but the risk of PTSD diagnoses for those prescribed mefloquine was statistically significantly increased relative to individuals who were prescribed A/P. There was no difference in PTSD diagnoses for deployed service members prescribed mefloquine compared with those prescribed doxycycline or A/P. When service members were stratified by prior psychiatric history, no statistically significant differences between meflo- quine and doxycycline use were found for PTSD diagnosis. However, Eick-Cost et al. did not present the data in a manner that allowed a separation of concurrent from persistent (≥28 days) psychiatric outcomes, although the authors stated that they performed a sensitivity analysis that restricted the risk period to 30 days post-cessation and that the results of those analyses were similar to what was presented. In their analysis of hospitalizations of active-duty service members, Wells et al. (2006) reported no statistically significant differences for PTSD diagnoses for deployed service members who were prescribed mefloquine versus deployed service members who did not use an antimalarial drug or who were assigned to Europe or Japan. In this study, only one diagnosis of PTSD was reported in the mefloquine group compared with 29 diagnoses in the deployed nonuser group and 38 diagnoses in the assigned-to-other-locations group. Likewise, in their study of U.S. veterans, Schneiderman et al. (2018) also found no difference in PTSD symptoms using a standardized instrument between mefloquine users and nonusers of antimalarials after controlling for demographics and deployment. No difference in PTSD was found between veterans who reported using mefloquine and another antimalarial and those with no antimalarial use after adjusting for demographics, deployment, and combat. In sum, most of the findings with respect to risk for PTSD in mefloquine users show no difference or a lower risk when they are compared with nonusers of antimalarials and those who received other drugs, after adjusting for deployment status. However, one analysis showed an increased risk of PTSD in mefloquine users relative to A/P users but only among those who were nondeployed; the implications of this are unclear. Based on the available evidence, the committee concludes that there is insufficient or inadequate evidence of an association between the use of mefloquine for malaria prophylaxis and persistent or latent psychiatric events, including PTSD. Current evidence suggests further study of such an association is warranted, given the evidence regarding biologic plausibility, adverse events associated with concurrent use, or data from the existing epidemiologic studies. Gastrointestinal Disorders The most recent FDA package insert for mefloquine states that the most frequently observed adverse event in clinical trials of malaria prophylaxis was

156 LONG-TERM HEALTH EFFECTS OF ANTIMALARIAL DRUGS vomiting (3%), while postmarketing surveillance found the most frequently reported gastrointestinal adverse events to be nausea, vomiting, loose stools or diarrhea, and abdominal pain, but the duration of such symptoms is not detailed. Systematic reviews of adverse events in travelers who used mefloquine compared with other regimens, placebo, or no antimalarial drug included concurrent gastrointestinal symptoms (abdominal discomfort or pain, anorexia, diarrhea, nausea, vomiting, dyspepsia). In the systematic review by Croft and Garner (2000), no consistent pattern was seen for the gastrointestinal symptoms analyzed, due in part to the heterogeneity of studies, but abdominal discomfort was reported statistically less frequently with other antimalarial drugs, as were anorexia and nausea. In a second systematic review examining the adverse events of mefloquine prophylaxis among travelers that included two randomized controlled trials and three cohort studies, mefloquine recipients were statistically significantly more likely to experience nausea than placebo recipients, but there was no difference between groups for vomiting, abdominal pain, or diarrhea. Based on cohort studies that compared mefloquine users with doxycycline users, mefloquine users were statistically significantly less likely to report dyspepsia and vomiting, but these results were given low or very low certainty of evidence, respectively. However, among pregnant women using mefloquine for intermittent preventive treatment in pregnancy, for which the dosage used is substantially higher than the dosage used for malaria prophylaxis, mefloquine was associated with a statistically significantly higher risk of drug-related vomiting and higher rates of nausea compared with use of sulfadoxine-pyrimethamine, but these symptoms all were reported to resolve spontaneously within 3 days. Published individual case reports that had follow-up of at least 28 days post- mefloquine-cessation did not report on gastrointestinal disorders. The FDA pack- age insert warns that mefloquine elimination may be prolonged in people who have impaired liver function, which may lead to higher plasma levels and a higher risk of adverse events. In a small study, DeSouza (1983) found that liver and spleen enlargement was reduced among the mefloquine participants (and sulfadoxine/ pyrimethamine participants) over the course of follow-up. In one case series (Croft and Herxheimer, 2002) that reviewed case reports of adverse event reports associ- ated with the use of mefloquine, the researchers hypothesized that adverse events may be due to liver or thyroid pathology; however, no objective validation of the adverse events reported by the cases or other follow-up was conducted, among other limitations of this analysis. Biologic plausibility data on gastrointestinal effects are lacking. While there is some evidence of mefloquine action on β-cells, no experimental studies have provided data on mechanisms to support the potential for observed gastrointestinal disorders to become persistent. The committee reviewed several epidemiologic studies that examined gastro- intestinal disorders and outcomes that occurred during or immediately after (within 28 days of) mefloquine use, but because they did not follow or report on these

MEFLOQUINE 157 adverse events 28 days post-cessation, the results are not considered to contribute to the evidence base of persistent gastrointestinal events post-mefloquine-use. Only Wells et al. (2006), based on the strength of the methods used in that analy- sis, was considered to provide robust evidence for gastrointestinal disorders that occurred or persisted at least 28 days following the cessation of mefloquine. Using ICD-9-CM codes, Wells et al. grouped disorders of the digestive system and found that 23 mefloquine users were hospitalized for these disorders. When mefloquine users were compared with deployed service members who were not prescribed an antimalarial, there was no difference in the risk of digestive system disorders, but compared with those service members who were assigned to Europe or Japan, deployed mefloquine users had a statistically significantly lower risk of hospital- ization for digestive system disorders. This study provides some evidence for an absence of increased risk for serious persistent digestive system disorders follow- ing the use of mefloquine, but it is unclear if some of these concurrent adverse events persisted or if concurrent events preceded persistent outcomes that may not resolve without additional treatment. Tan et al. (2017) lends additional weak sup- port (given its serious methodologic limitations) to an absence of increased risk of persistent gastrointestinal disorders following use of mefloquine. Based on the available evidence, the committee concludes that there is insuf- ficient or inadequate evidence of an association between the use of mefloquine for malaria prophylaxis and persistent or latent gastrointestinal events. Current evidence does not suggest further study of such an association is warranted, given the lack of evidence regarding biologic plausibility, adverse events associated with concurrent use, or findings from the existing epidemiologic studies. Eye Disorders Although there are reports of concurrent visual disturbance including optic neuropathy and retinal disorders associated with mefloquine use (FDA, 2016; Tickell-Painter et al., 2017a), in the epidemiologic studies that examined persistent eye disorders, these effects were not observed to occur at statistically different rates for mefloquine users than for people who used other antimalarial drugs or who did not use any prophylaxis. Among the case reports, concurrent adverse events included visual illusions and one case of persistent retinopathy. A large analysis of eye disorders associated with mefloquine use reported to the manufac- turer’s drug safety database provides additional indirect support for adverse events of visual acuity and disorders affecting the retina or cornea (Adamcova et al., 2015). In addition to the available data on eye disorders in humans, experimental data may support plausible biologic mechanisms for mefloquine affecting ocular components, acting via a disruption of connexin signaling in the lens and possible phototoxic changes in the retina. Of the 11 epidemiologic studies on persistent adverse events, 2 made a men- tion of eye disorders that occurred at least 28 days following the cessation of meflo-

158 LONG-TERM HEALTH EFFECTS OF ANTIMALARIAL DRUGS quine (Schneider et al., 2014; Tan et al., 2017). Given the serious ­ ethodologic m limitations of Tan et al. (2017), only Schneider et al. (2014) was considered, based on the strength of the methods used in that analysis, to provide robust evidence for persistent ophthalmic outcomes. Schneider et al. (2014) assessed incident diagnoses of eye disorders among travelers aged ≥1 year who had been prescribed mefloquine and compared them with two other groups of travelers: travelers who had been prescribed another antimalarial and travelers who had a travel consult but were not prescribed antimalarial drugs. Eye disorders were grouped into eight categories, some specific (such as cataract, glaucoma, and vitreous detachment) and others a compilation of disorders of the cornea, retina, visual acuity, uvea, and neuro-ophthamology. The timing of incident diagnoses was stratified into “current use,” which mixed irrelevant (7–28 days post-cessation) and relevant (28–90 days post-cessation) time periods, and “past use” (91–540 days post-cessation), all of which was relevant. Over the approximately 8.5-year period of data examined, a total of 85 people who had used mefloquine were diagnosed with an incident eye disorder of interest; 23 incident eye disorders were found for current users, and 62 were found for past users. A nested case–control analysis found that the odds of developing any of the eye disorders of interest were statistically signifi- cantly elevated for mefloquine users compared with travelers who did not use any antimalarial drugs. However, when mefloquine use was stratified by current use and past use and the users compared with the nonusers, there was no statistically significant difference for current users, although past users had statistically signifi- cantly increased odds of experiencing any eye disorder when all were grouped as a single category. When each of the individual eye disorders was examined without timing stratification, only cataract was statistically significantly related to meflo- quine use compared with no use of antimalarials. Other risk factors for cataracts, such as occupation and sun exposure, were not included in the analysis and may have differed between the groups. Overall, this was a well-designed study, and the stratification of past use in particular provides some evidence for an absence of increased risk of persistent eye disorder diagnoses following the use of mefloquine. The findings of no differences in risk of ophthalmologic disorders of macular degeneration, retinopathy, and “any” ophthalmologic disorder by Tan et al. (2017) provide additional weak supportive evidence of an absence of increased risk of eye disorders. However, the finding of increased risk of cataracts with mefloquine use in Schneider et al. (2014) requires confirmatory evidence. Based on the available evidence, the committee concludes that there is insuf- ficient or inadequate evidence of an association between the use of mefloquine for malaria prophylaxis and persistent or latent eye disorders, including cataract. Current evidence suggests further study of such an association is warranted, given the evidence regarding biologic plausibility, adverse events associated with concurrent use, or findings from the existing epidemiologic studies.

MEFLOQUINE 159 Cardiovascular Disorders The most recent FDA package insert for mefloquine states that syncope and extrasystoles were reported in less than 1% of mefloquine users participating in clinical trials of malaria prophylaxis. Other concurrent adverse events reported with the use of mefloquine have included transitory and clinically silent ECG alterations such as sinus bradycardia, sinus arrhythmia, first degree AV block, pro- longation of the QTc interval, and abnormal T-waves. Among the case reports that followed outcomes at least 28 days post-cessation of mefloquine, heart palpitations were reported in one case in which concurrent symptoms of paralysis and trouble breathing were also reported (Eaton, 1996). The available biologic plausibility data on cardiovascular effects are limited, but some data suggest that mefloquine may induce cardiovascular effects through the inhibition of several cardiac potassium channels. Mefloquine may also affect intracellular calcium homeostasis in cardiac myocytes, suggesting some potential for cardiac indications, although this was not tested in the context of persistent or latent actions. The committee reviewed four epidemiologic studies that examined cardio­ vascular or circulatory system outcomes that occurred at least 28 days following the cessation of mefloquine (DeSouza, 1983; Laothavorn et al., 1992; Tan et al., 2017; Wells et al., 2006). Similar to the other body system outcome categories, cardiovascular and circulatory system outcomes were inconsistently identified and measured across studies. DeSouza (1983) used ECGs and measured blood pressure and pulse rate, as well as hematologic parameters of red blood cell count, hemoglobin erythrocyte volume fraction, total and differential white blood cell counts, reticulocyte count, and platelet count. Measurements of other biochemical p ­ arameters (including cholesterol, triglycerides, glucose, urea, creatinine, etc.) in sera were also performed. Laothavorn et al. (1992) also used ECGs to measure heart rate and different cardiac intervals and to diagnose abnormalities of sinus bradycardia, sinus arrhythmia, ventricular ectopic beats, atrial ectopic beats, atrial– ventricular block, and heart rate; they also performed weekly blood count tests. The two other studies (Tan et al., 2017; Wells et al., 2006) grouped cardio­ ascular v outcomes. In Tan et al. the cardiac category included arrhythmia, congestive heart failure, myocardial infarction, and “any” cardiac disorder, while Wells et al. grouped outcomes by ICD-9-CM code into disorders of the blood and blood- forming organs and a separate category of disorders of the circulatory system. While none of these studies is without methodologic limitations, Wells et al. (2006) provided the most robust evidence regarding persistent cardiovascular and circulatory system outcomes. In short, only four hospitalizations related to blood and blood-forming organs (ICD-9-CM: 280–289) and nine hospitalizations from circulatory system disorders (ICD-9-CM: 390–459) were reported for mefloquine users. Comparisons with both reference groups showed that mefloquine users had no difference in risk for both groups of disorders, providing some evidence for an absence of increased risk of persistent disorders of blood or blood-forming organs

160 LONG-TERM HEALTH EFFECTS OF ANTIMALARIAL DRUGS or the cardiovascular system following use of mefloquine. The results from the three other epidemiologic studies lend additional support, although of less weight, for an absence of increased persistent cardiovascular events. Tan et al. (2017) reported that there were no statistically significant differences in cardiac outcomes between users of mefloquine and of the other antimalarial drugs for prophylaxis, but they did not provide frequencies of the events or effect estimates. Although both DeSouza (1983) and Laothavorn et al. (1992) used objective tests (ECGs) and standard hematologic and laboratory measures in their investigations, the presented results are not readily comparable between studies and were sometimes vague. DeSouza stated that blood pressure, pulse rate, and ECG remained normal throughout the study period (63 days after mefloquine administration), but no other details regarding the ECG results were provided. Hematologic tests were conducted several times throughout the study, but only those taken on days 28 and 63 post-administration were relevant to the committee’s work. No significant adverse changes were reported for any of the collected parameters for the group administered mefloquine. Laothavorn et al. performed ECGs on healthy volunteers prior to mefloquine administration, daily for 1 week post-administration, and then weekly until day 42 post-administration. All ECG parameters were reported to be within normal limits, and no changes in biochemical or hematologic mea- sures were found following mefloquine administration. Although the results from the DeSouza and Laothavorn studies appear to be consistent with an absence in increased persistent events of cardiovascular or circulatory disorders following use of mefloquine—especially considering that the administered doses of mefloquine were 3–4 times higher than the dose used for prophylaxis—both of these studies were small and underpowered and were limited in the information reported. The concurrent events listed in the FDA package insert were not found to occur in the epidemiologic studies that measured them. Based on the available evidence, the committee concludes that there is ­nsufficient or inadequate evidence of an association between the use of mefloquine i for malaria prophylaxis and persistent or latent cardiovascular events. Current evidence does not suggest further study of such an association is warranted, given the lack of evidence regarding biologic plausibility, adverse events associated with concurrent use, or findings from the existing epidemiologic studies. Other Outcomes and Disorders In addition to those outcomes synthesized above, two of the epidemiologic studies examined other outcomes and disorders that occurred at least 28 days following the cessation of mefloquine. Tan et al. (2017) included dermatologic outcomes as a group that included allergic dermatitis, eczema, psoriasis, “other” and “any” dermatologic conditions and reported that there were no statistically significant differences between users of mefloquine and those of the other anti- malarial drugs for prophylaxis, but neither the frequencies of such events nor

MEFLOQUINE 161 effect estimates were provided. Wells et al. (2006) reported nine hospitalizations from skin and subcutaneous tissues (ICD-9-CM: 680–709) among mefloquine users in their study of U.S. service members, but no difference in risk was found between deployed service members who were prescribed mefloquine and those who were not prescribed an antimalarial. In one systematic review, reports of fever and ­ ruritus were similar in the mefloquine and comparator arms (Croft p and Garner, 2000). In a second systematic review, skin and subcutaneous tissues outcomes (pruritus, photosensitivity, vaginal candida) were examined, and based on data from cohort studies, mefloquine users were statistically significantly less likely than doxycycline users to report photosensitivity or vaginal thrush, but both findings were based on very low-certainty evidence. In the case reports, one case of worsening psoriasis was reported (Potasman and Seligmann, 1998). In a case series (Smith et al., 1999) of 74 published case reports of mefloquine use (pro- phylaxis or treatment) specific to dermatologic adverse events, the timing of onset of dermatologic effects was only recorded in 11 of the cases; pruritus and itching were reported in more than 40% of all the cases. Most effects were reported as mild or moderate in intensity and usually self-limiting, although the timing was not specified. Other dermatologic adverse events in this case series included two reports of cutaneous vasculitis and one report each of Stevens-Johnson syndrome and toxic epidermal necrolysis. In sum, several studies of varying quality have examined skin disorders associated with the use of mefloquine, but taken as a whole there is some evidence for an absence of increased risk of persistent skin and subcutaneous tissue disorders following use of mefloquine. Wells et al. (2006) also reported hospitalizations for other system disorders among active-duty U.S. service members. In total, 135 hospitalizations for any cause were reported among mefloquine users, but there was no statistical differ- ence in the risk compared with deployed service members who were not prescribed an antimalarial. Hospitalizations related to categories of infections; neoplasms; disorders of endocrine, nutritional, or metabolism; disorders of the respiratory system; disorders of the genitourinary system; disorders of musculoskeletal and connective tissue; ill-defined conditions; and injury and poisoning were also examined and compared between mefloquine users and the two reference groups. Comparisons of mefloquine users with deployed service members who were not prescribed an antimalarial resulted in a mix of increased and decreased effect estimates for categories of neoplasms; disorders of endocrine, nutritional, or metabolism; disorders of the respiratory system; disorders of the genitourinary system; disorders of musculoskeletal and connective tissue; ill-defined condi- tions; and injury and poisoning, but none reached statistical significance. Although methodologically limited, Tan et al. (2017) reported that reproductive outcomes (miscarriage), infections (amebiasis, giardia, “other” and “any” gastrointestinal infection), and hematologic/oncologic disorders (breast cancer, gastric cancer, leukemia, liver cancer, lymphoma, prostate cancer, “other” and “any” cancers) were not statistically significantly different between users of mefloquine and the

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Among the many who serve in the United States Armed Forces and who are deployed to distant locations around the world, myriad health threats are encountered. In addition to those associated with the disruption of their home life and potential for combat, they may face distinctive disease threats that are specific to the locations to which they are deployed. U.S. forces have been deployed many times over the years to areas in which malaria is endemic, including in parts of Afghanistan and Iraq. Department of Defense (DoD) policy requires that antimalarial drugs be issued and regimens adhered to for deployments to malaria-endemic areas. Policies directing which should be used as first and as second-line agents have evolved over time based on new data regarding adverse events or precautions for specific underlying health conditions, areas of deployment, and other operational factors

At the request of the Veterans Administration, Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis assesses the scientific evidence regarding the potential for long-term health effects resulting from the use of antimalarial drugs that were approved by FDA or used by U.S. service members for malaria prophylaxis, with a focus on mefloquine, tafenoquine, and other antimalarial drugs that have been used by DoD in the past 25 years. This report offers conclusions based on available evidence regarding associations of persistent or latent adverse events.

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