Throughout the remainder of the 1990s, mefloquine remained the antimalarial drug of choice for most U.S. military operations, and when combat began in Afghanistan in 2001, widespread use was also directed there.12,13 The following year, after national attention was directed to concerns of severe behavioral toxicity from the drug among personnel returning from Afghanistan, the manufacturer issued subtle changes to the mefloquine label warnings.5,14
These label changes adjusted the previously exclusive list of prodromal symptoms to an illustrative list, emphasizing that “if psychiatric symptoms such as [emphasis added] acute anxiety, depression, restlessness or confusion occur, these may be considered prodromal to a more serious event. In these cases, the drug must be discontinued and an alternative medication should be substituted.”5
In 2001 a randomized double-blinded trial demonstrated that symptoms of anxiety and depression occurred in at least 4% of mefloquine users, insomnia in 13%, and abnormal dreams in 14%. Nevertheless, an Army memorandum issued soon after the labeling change significantly understated the known risks of developing such psychiatric symptoms, erroneously claiming that these occurred from mefloquine only “at a rate of one per 2,000 to 13,000 persons.”15,16
Updated FDA Guidelines
In 2003, with widespread use of the drug being again directed during operations in Iraq, the FDA required that all mefloquine prescriptions be accompanied by a patient medication guide with warnings echoing those of the drug label that users seek medical attention should “possible signs of more serious mental problems” develop.5,17 However, surveys suggested that few U.S. service members received these warnings or even verbal instructions to that effect.17-19 During later congressional testimony, a service member who had experienced 3 weeks of nightmares prior to self-discontinuing the drug testified “every soldier I know has problems with it.”20
In response, a senior military medical leader—failing to recognize that the nightmares the soldier reported were in fact psychiatric symptoms and possible signs of more serious mental problems that required the drug’s discontinuation—may have undermined the FDA-directed warnings by dismissing the soldier’s testimony as “perception,” maintaining instead “that perceptions can become realities” should it become “held that this medication is widely problematic.”20
Given that certain preexisting conditions, including anxiety and depression, were known to confound recognition of incident psychiatric symptoms that required discontinuation of the drug, the original 1989 mefloquine label had noted that the drug should be used with caution in such patients. In subsequent years, this language was strengthened, and such patients were formally contraindicated the drug.21
Citing formal policy, senior military medical leaders provided assurance during congressional testimony that service members with these conditions would not be prescribed mefloquine.16,18,20 However, later analysis of a large group of deployed service members revealed that 1 in 7 with contraindications to mefloquine had been prescribed the drug contrary to drug label guidance.21
Black Box Warning
With growing recognition of the challenges in using mefloquine as directed by the drug label, a 2009 Army policy memorandum prioritized the use of safer and better-tolerated daily medications, such as doxycycline and atovaquone-proguanil, and stated that “[m]efloquine should only be used for personnel with contraindications to doxycycline.”22 This policy was extended throughout the other military services later that year.23 After concerns were raised that service members were still being prescribed the drug contrary to policy, further restrictions were formalized in early 2013 prior to the boxed warning, with mefloquine reserved for those only “with intolerance or contraindications” to the first-line drugs.24,25
In a later memorandum announcing the July 2013 boxed warning, the military revealed that the number of active-duty personnel prescribed mefloquine had steadily decreased in prior years from 17,361 in 2008 to only 2,040 in 2012.7 Although the military has not released precise figures on the number of U.S. military personnel exposed to mefloquine since the drug’s introduction, based on a variety of sources, the total is likely to far exceed 100,000.7,26
The major changes to the mefloquine label in 2013, including the boxed warning, clarified that neurologic and psychiatric effects from mefloquine could “persist after mefloquine has been discontinued.” The accompanying FDA Drug Safety Communication noted neurologic AEs from the drug, which include but are not limited to “dizziness, loss of balance, or ringing in the ears,” could “occur at any time during drug use, and can last for months to years after the drug is stopped or can be permanent.”6 Other neurologic symptoms listed in the drug label include vertigo, hearing impairment, headache, visual disturbances, sensory and motor neuropathies, including paresthesia, tremor, ataxia, convulsions, and encephalopathy.6
The updated drug label also made clear that psychiatric AEs from mefloquine, such as anxiety, paranoia, and depression to hallucinations and psychotic behavior, “have been reported to continue for months or years after mefloquine has been stopped.” Other psychiatric symptoms listed in the drug label include memory impairment, confusion, somnolence, insomnia, abnormal dreams, aggression, agitation, restlessness, mood swings, panic attacks, psychosis, and suicidal ideation.6
The 2013 boxed warning also served to reemphasize guidance first articulated in 2002 that any psychiatric symptom—presumably including abnormal dreams and insomnia—occurring during mefloquine use should be considered prodromal, prompting the drug’s immediate discontinuation.5 Specifically, the boxed warning explicitly cautioned that given the risk for serious psychiatric disturbances or neurologic AEs when used for malaria prophylaxis, “if psychiatric or neurologic symptoms occur, the drug should be discontinued and an alternative medication should be substituted.”6