Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis (2020) / Chapter Skim
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4 Mefloquine
4 Mefloquine
Pages 91-176
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From page 91... ...
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)
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Supplemental supporting evidence is then presented, including other identified 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.
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People with contraindications to mefloquine were twice as likely to be prescribed a different antimalarial drug, but occasionally people with contraindications were prescribed mefloquine (Bloechliger et al., 2014)
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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)
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The 2013 drug safety communication states: "In conducting its assessment 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 vestibular symptoms such as dizziness, loss of balance, tinnitus, and vertigo." It notes further 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)
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is a drug safety program that FDA requires for certain medications with serious safety concerns. They are designed to help reduce the occurrence and/or severity of certain serious risks and to ensure the benefits of the medication outweigh
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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)
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. 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)
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. Regarding adverse events, the package insert states that the most frequently observed adverse event in clinical trials of malaria prophylaxis was vomiting (3%)
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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.
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From page 101... ...
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)
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From page 102... ...
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)
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Since 2015 the governments of Australia, Canada, and the United Kingdom have performed inquiries or investigations into the possible 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)
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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.)
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. 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)
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The other prophylactic 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)
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. Instead of detailing every study that has reported concurrent adverse events that have been reported with use of mefloquine, the following 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)
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This p review included 20 randomized controlled trials (totaling 11,470 participants) , 35 cohort studies (totaling 198,493 participants)
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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)
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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.
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. 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)
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Effect estimates of neurologic and psychiatric outcomes for oxycycline and A/P are reported in those respective chapters. For mefloquine users d
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, 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.
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(2018) conducted a retrospective observational analysis of self-reported health outcomes associated with use of antimalarial drugs in a cohort of U.S.
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In the adjusted logistic regression models with all covariates considered (including 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)
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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 activeduty 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)
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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 considered, 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 syndromes, 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.
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. 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)
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, 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 relative to individuals who did not take mefloquine (prevalence ratio = 1.15, 95%CI 1.07–1.23)
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-- 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)
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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.
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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)
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Current mefloquine users had statistically significantly lower odds of developing depression than non-antimalarial users (OR = 0.32, 95%CI 0.19–0.54)
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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 outcomes for mefloquine users versus the unexposed group suggests the possibility of uncontrolled confounding by contraindication.
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Compared with travelers who did not use any antimalarial drugs, the odds of developing any of the eye disorders of interest were elevated for mefloquine users combined (OR = 1.33, 95%CI 1.01–1.75)
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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.
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. 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.
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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.
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From page 129... ...
for malaria prophylaxis in Australian soldiers; however, because the mefloquine comparison group also used primaquine, it was not considered 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-mefloquinecessation 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)
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(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 Thailand who were followed for 4 weeks after the final dose.
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. 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.
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(2015) performed an analysis of eye disorders associated with the prophylactic use of mefloquine.
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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.
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associated with mefloquine 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.
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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.
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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.
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. Mefloquine is not as well tolerated as other antimalarial drugs when used for intermittent preventive treatment in pregnancy (IPTp)
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. In a comparison of neurologic and psychiatric outcomes among mefloquine users (n = 58)
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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.
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(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 mefloquine group was statistically significantly higher than the group who did not use antimalarials (p = 0.01)
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, 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 mefloquine concentrations substantially exceeded the highest plasma levels (4.5 µM)
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. For example, mefloquine administration in rats can impair the processing of contextual fear, impairing retrieval and enhancing extinction of freezing responses to the fearful context via inhibition of connexins (Bissiere et al., 2011)
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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.
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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)
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Epidemiologic Studies Presenting Contributory Evidence Eick-Cost used DoD administrative databases to perform a large retrospective 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 recurrent 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.
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From page 146... ...
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.
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. 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.
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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.
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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.
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From page 150... ...
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)
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The most weight for evidence of an association between use of mefloquine and persistent or latent psychiatric adverse events comes from the seven epidemiologic 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)
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From page 152... ...
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 differences were found for the other five psychiatric outcomes.
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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 confound associations between the use of mefloquine and adverse psychiatric events, such as deployment and combat exposure, are rarely encountered with leisure ravelers.
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(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.
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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
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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.
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, 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.
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From page 158... ...
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 significantly elevated for mefloquine users compared with travelers who did not use any antimalarial drugs.
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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
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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.
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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)
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2004. Photophysical and photobiological behavior of antimalarial drugs in aqueous solutions.
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Travel Med Infect Dis 12(6)
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Travel Med Infect Dis 12(4)
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in malaria prophylaxis (September 4, 2009, #HA 09-017)
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2013a. FDA drug safety communication: FDA approves label changes for antimalarial drug mefloquine hydrochloride due to risk of serious psychiatric and nerve side effects.
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2016. Adverse neuropsychiatric effects of antimalarial drugs.
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Trans R Soc Trop Med Hyg 100(6)
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2003. Trends in antimalarial drugs prescribed in Australia 1992 to 1998.
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1999. Photophysical studies on antimalarial drugs.
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. Trans R Soc Trop Med Hyg 93(1)
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Travel Med Infect Dis 13(1)
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2016. The interactions of P-glycoprotein with antimalarial drugs, including substrate affinity, inhibition, and regulation.
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2008. Antimalarial drugs inhibit human 5-HT(3)
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2002b. Atovaquone plus chloroguanide versus mefloquine for malaria prophylaxis: A focus on neuropsychiatric adverse events.
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Presentation to the Committee to Review Long-Term Health Effects of Antimalarial Drugs on January 28, 2019. Wittes, R
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