Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis (2020) / Chapter Skim
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6 Atovaquone/Proguanil
6 Atovaquone/Proguanil
Pages 217-246
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From page 217... ...
. Proguanil continues to be used in other countries in combination with other antimalarial agents, such as chloroquine, for malaria prophylaxis.
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From page 218... ...
The known mechanisms of action of A/P are then described, including its pharmacokinetic properties. Known concurrent adverse events associated with the use of A/P when used at the directed dose and interval for malaria prophylaxis are summarized, followed by detailed summaries and assessments of the post-cessation epidemiologic studies that contributed some information on persistent or latent health outcomes of A/P.
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From page 219... ...
. The regimen for A/P requires individuals to take the drug for only 7 days after leaving an endemic area; this is a much shorter period than required for other suppressive antimalarial drugs, such as doxycycline, which requires individuals to take the drug for 28 days after leaving an endemic area.
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From page 220... ...
Clinical trial data were added, showing the frequency of adverse experiences in subjects receiving A/P was similar to or less than that in individuals receiving mefloquine or chloroquine plus proguanil; more specifically, fewer neuropsychiatric adverse events occurred with A/P than with mefloquine, fewer gastrointestinal adverse events occurred than with chloroquine/ proguanil, and fewer adverse experiences overall than with both comparators. In 2004 the Postmarketing Adverse Reactions section added "rare cases of seizures and psychotic events (such as hallucinations)
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From page 221... ...
. "Rare cases of vasculitis" was amended to "vasculitis"; angioedema and "rare cases of anaphylaxis" were deleted; and "rare cases of seizures and psychotic events" was amended to delete "rare." The 2013 label added animal studies that found no adverse fertility or pre/post-natal adverse events in animals given proguanil hydrochloride at lower than prophylactic-equivalent doses, but it noted that studies of proguanil in animals at exposures similar to or greater than those observed in humans had not been conducted (FDA, 2013)
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From page 222... ...
Epidemiologic studies of persistent or latent adverse events in which information was presented regarding adverse events occurring at least 28 days post-A/P-cessation are then summarized, with the emphasis on reported results of persistent or latent adverse events associated with the use of A/P, including the results of studies in which other antimalarial drugs were used as a comparison group. Concurrent Adverse Events The most commonly observed concurrent adverse events associated with A/P use are mild or moderate in nature and include nausea, vomiting, abdominal pain, headache, stomatitis, and diarrhea (Boggild et al., 2007; Castelli et al., 2010; Schlagenhauf et al., 2019)
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From page 223... ...
. In the single included trial, mefloquine users were statistically significantly more likely than A/P users to report psychiatric adverse events of abnormal dreams, insomnia, anxiety, and depressed mood.
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From page 224... ...
The primary study objective was to assess and compare the risk of incident and recurrent International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) -coded neurologic and psychiatric outcomes (adjustment disorder, anxiety disorder, depressive disorder, posttraumatic stress disorder [PTSD]
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From page 225... ...
. With few exceptions, the adjusted incident rates were higher among the deployed than among the nondeployed for A/P as well as for the other antimalarial drugs considered.
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From page 226... ...
to compare the prevalence of selected health conditions after Peace Corps service between those who reported taking malaria prophylaxis (n = 5,055; 56.6%) and those who did not.
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From page 227... ...
and non-exposure. Thus, 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.
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From page 228... ...
-- which has since changed names to the Clinical Practice Research D atalink -- to assess the incidence and compare the odds of developing first-time neurologic, psychiatric, or eye disorders in individuals using A/P 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; these studies have included investigations of drug safety, the use of medications, health care delivery, and disease risk factors (CPRD, 2019)
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From page 229... ...
for malaria prophylaxis or else no antimalarial prescription (but who had a pre-travel consultation)
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From page 230... ...
, depression, epilepsy, or peripheral neuropathy associated with A/P use for malaria prophylaxis in travelers aged ≥1 year when assessing current use and 18 months following current use.
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From page 231... ...
A nested case–control analysis was performed in which smoking, 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 interest was elevated for A/P users (OR = 1.25, 95%CI 1.03–1.52)
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From page 232... ...
Case Reports and Case Series A/P is relatively well tolerated, but a few moderate to severe adverse events have been reported in individuals using A/P for malaria prophylaxis. The committee reviewed three case reports, totaling three patients, which reported adverse events that persisted for at least 28 days following A/P cessation.
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From page 233... ...
This was not done exhaustively, and the evidence included in this section is generally limited to concurrent adverse events observed with A/P use. Many of these studies did not meet the inclusion criteria of following their population for at least 28 days post-A/P-cessation, but the committee considers these findings to be important indicators when considering the evidence as a whole.
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From page 234... ...
. Based on the paucity of currently available scientific literature examining the biologic plausibility of persistent or latent adverse events resulting from the use of A/P for malaria prophylaxis, the committee found minimal to no evidence
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From page 235... ...
. While there have been several studies of concurrent adverse events when using A/P for malaria prophylaxis, the evidence addressing latent or persistent adverse events is quite limited in quantity and quality.
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From page 236... ...
The synthesis of evidence is followed by a conclusion of the strength of evidence regarding an association between the use of A/P and persistent or latent adverse events and whether the available evidence would support additional research into those outcomes. The outcomes are presented in the following order: neurologic disorders, psychiatric disorders, gastrointestinal disorders, eye disorders, cardiovascular disorders, and other outcomes.
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From page 237... ...
Two large, retrospective studies of travelers (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 aged ≥1 year using A/P compared with other antimalarial drugs for malaria prophylaxis relative to travelers who did not use an antimalarial.
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From page 238... ...
Based on the available evidence, the committee concludes that there is insufficient or inadequate evidence of an association between the use of ato vaquone/proguanil for malaria prophylaxis and persistent or latent neurologic 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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From page 239... ...
. A Cochrane systematic review of concurrent adverse events in short-term travelers using mefloquine compared with other antimalarials, including A/P, found that mefloquine users were statistically significantly more likely than A/P users to report the psychologic adverse events of abnormal dreams, insomnia, anxiety, and depressed mood in one trial, and consistent, larger effects were observed in the included cohort studies.
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From page 240... ...
Based on the available evidence, the committee concludes that there is insufficient or inadequate evidence of an association between the use of atovaquone/ proguanil for malaria prophylaxis and persistent or latent psychiatric events. C urrent 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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From page 241... ...
Eye Disorders The FDA label is silent on eye disorders, and no case studies of latent or persistent eye disorders were identified. A Cochrane systematic review of concurrent adverse events in short-term travelers using A/P compared with mefloquine found that, based on one trial and two cohort studies, there was no difference between A/P users and mefloquine users in experiencing visual impairment (Tickell-Painter et al., 2017)
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From page 242... ...
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 None of the three high-quality epidemiologic studies reviewed (Eick-Cost et al., 2017; Schneider et al., 2013, 2014)
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From page 243... ...
Travel Med Infect Dis 12(4)
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From page 244... ...
Food and Drug Administration–approved antimalarial drugs. Clin Infect Dis 43(1)
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From page 245... ...
Travel Med Infect Dis 11(2)
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From page 246... ...
2017. Long term health outcomes among returned Peace Corps volunteers after malaria prophylaxis, 1995–2014.
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