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6 Atovaquone/Proguanil The fixed-dose combination of 250 mg atovaquone and 100 mg proguanil hydrochloride (A/P; trade name MalaroneÂ® by GlaxoSmithKline) was approved by the Food and Drug Administration (FDA) for the prophylaxis and treatment of malaria in 2000. Proguanil and an analog of atovaquone were first identified as potential antimalarial agents during the U.S. Armyâs drug discovery and develop- ment program during World War II (Arguin and Magill, 2017). In 1945 the first published study of proguanil reported that it was more active than quinine against avian malaria and had a better therapeutic index in animal models, prompting its use in humans (Nzila, 2006). Proguanil was approved in 1948 by FDA for use in humans as an antimalarial agent, but it was not widely used. In the 1950s the first reports of Plasmodium parasite resistance to proguanil when taken as monotherapy occurred; the United States stopped marketing proguanil as a single drug in the 1970s (Kitchen et al., 2006; Looareesuwan et al., 1996). Proguanil continues to be used in other countries in combination with other antimalarial agents, such as chloroquine, for malaria prophylaxis. Once proguanil was discovered, investigated, and approved for use in the United States, other compounds, including hydroxynaphthoquinones such as atovaquone, which had been identified during the drug discovery program of World War II and had demonstrated activity against the P. falciparum parasite were not investigated further for several years. In the 1980s a group at Wellcome Research Â aboratories L reinvestigated the hydroxynaphthoquinone lapinone, an atovaquone analog, as an antimalarial agent (Nixon et al., 2013). As a result of its efforts, atovaquone was identified as an antimalarial drug candidate and in 1995 was approved for use as a monotherapy (FDA, 2019b; Nixon et al., 2013). The combination of A/P was cre- ated as a result of the emergence of resistance to proguanil and Â tovaquone in the a 217
218 LONG-TERM HEALTH EFFECTS OF ANTIMALARIAL DRUGS 1940s and 1990s, respectively. Atovaquone is no longer used as a monotherapy to treat or prevent malaria because one-third or more of individuals with P. falciparum infections will recrudesce (Srivastava and Vaidya, 1999). Both drugs had been highly effective as single agents, and after laboratory testing it was discovered that they demonstrated a synergistic effect on the malaria parasite (Gorobets et al., 2017). Individuals infected with malaria that was resistant to atovaquone and proguanil as single agents could effectively take A/P as a combination for malaria prophylaxis. Although A/P was approved by FDA in 2000, it has been used in military populations since 1997, and it is considered a first-line drug for malaria prophylaxis.1 Because of the higher cost of A/P compared with other antimalarial drugs, individuals are sometimes unable or reluctant to use it (Castelli et al., 2010). This chapter begins with a brief description of the key changes that have been made to the FDA package insert and label for A/P since its approval in 2000, with a particular emphasis on changes to the Warnings, Precautions, and Contra- indications sections. The known mechanisms of action of A/P are then described, including its pharmacokinetic properties. Known concurrent adverse events asso- ciated 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. As in the other chapters, the epidemio- logic studies are organized by population: first, studies of military and veterans, followed by studies of members of the U.S. Peace Corps and then of travelers. A table that gives a high-level comparison of each of the four epidemiologic studies that examined the use of A/P and that met the committeeâs inclusion criteria is presented in Appendix C. Next, supplemental supporting evidence is presented, including other identified studies of health outcomes in populations that used A/P for prophylaxis but that did not meet the committeeâs inclusion criteria regarding the timing of follow-up, and information on adverse events of A/P use in specific groups, such as pregnant women and individuals with chronic health conditions. After presenting the primary and supplemental evidence in humans, the supporting literature from experimental animal and in vitro studies is then summarized. The chapter ends with a synthesis of all of the evidence presented and the inferences and conclusions that can be made from the available evidence. FOOD AND DRUG ADMINISTRATION PACKAGE INSERT FOR ATOVAQUONE/PROGUANIL The recommended A/P dosing regimen for malaria prophylaxis in adults begins with taking one tablet (250 mg atovaquone and 100 mg proguanil) by 1â Overview of DoD antimalarial use policies. Presentation to the committee, COL Andrew Wiesen, M.D., M.P.H., Director, Preventive Medicine, Health Readiness Policy, and Oversight, Office of the Assistant Secretary of Defense (Health Affairs), January 28, 2019.
ATOVAQUONE/PROGUANIL 219 mouth 1â2 days before entering a malaria-endemic area, taking one tablet daily at the same time each day throughout the entire stay in the endemic area, and continu- ing for 7 days after leaving the endemic area (FDA, 2019a). It is recommended that the drug be taken with food or a milky drink to increase its absorption and efficacy and to decrease the risk of gastrointestinal adverse events. If an individual vomits within 1 hour of taking A/P, another dose should be taken. Studies of drug adherence have found that the percentage of individuals Âaking t A/P who were adherent to the drug regimen was higher than the percentage of individuals taking other antimalarial prophylactic drugs (Goodyer et al., 2011). This is likely due to individuals using A/P having fewer acute adverse events than individuals using other prophylactic drugs. Even greater tolerance has been reported when A/P is taken with food (HÃ¸gh et al., 2000; Kain et al., 2001). Although a Cochrane systematic review of randomized trials and observational studies that compared mefloquine to A/P found no difference in adherence between the drugs (Â ickell-Painter et al., 2017), other reports indicate A/P is less likely to be discon- T tinued due to adverse events than other antimalarial prophylactic drugs, such as mefloquine (Kain et al., 2001; Overbosch et al., 2001; Tickell-Painter et al., 2017). The regimen for A/P requires individuals to take the drug for only 7 days after leav- ing 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. Because of the shorter duration required after leaving an endemic area, the A/P regimen has also been shown to have very high post-travel adherence compared with mefloquine (Â verbosch et al., 2001). O This section describes selected information that can be found in the FDA label or on the package insert for A/P. It begins with a summary of contraindications, warnings, and precautions for its use based on the most recent FDA label and package insert. This is followed by a brief synopsis of drug interactions known or presumed to occur with short-term A/P use. The final subsection provides a sum- mary of major changes to the label or package insert from its approval in 2000 to the most recent label, updated in 2019. The presented changes are specific to A/P when used for prophylaxis (not treatment) in adults (not infants or children). Contraindications, Warnings, and Precautions The package insert states, âA/P is contraindicated in individuals with known hypersensitivity reactions (e.g., anaphylaxis, erythema multiforme or Stevens-Â Johnson syndrome, angioedema, vasculitis) to atovaquone or proguanil hydrochlo- ride or any component of the formulationâ (FDA, 2019a). A/P is also contraindicated for prophylaxis of P. falciparum malaria in patients with severe renal impairment (creatinine clearance <30 mL/min) because of pancytopenia in patients with severe renal impairment treated with proguanil. Users are warned that there have been reports of elevated liver laboratory tests and cases of hepatitis and one account of hepatic failure requiring liver transplantation in persons using A/P as prophylaxis.
220 LONG-TERM HEALTH EFFECTS OF ANTIMALARIAL DRUGS Drug Interactions The concomitant use of A/P and rifampin or rifabutin is not recommended because the antibiotics reduce atovaquone plasma concentrations (FDA, 2019a). Caution should be exercised when using warfarin and other coumarin-based anti- coagulants when starting or stopping A/P use; proguanil can increase their antico- agulant effects, and the results of coagulation tests should be monitored closely. Concomitant use of tetracycline is associated with reduced plasma concentrations of atovaquone, so parasitemia should be monitored closely. Metoclopramide may decrease the bioavailability of atovaquone and thus should be used in A/P recipients only if other antiemetics are unavailable. Prescribing indinavir and ato- vaquone should be done with caution owing to the resulting reduction in trough concentrations of indinavir. Changes to the Atovaquone/Proguanil Package Insert Over Time A/P, marketed under the trade name MalaroneÂ®, was approved in 2000, and the most recent label was issued in 2019. It is possible that not all label updates made between 2000 and 2002 are posted on the Drugs@FDA Search site. A comparison of the original label with the posted 2002 label (a version that contained underlin- ing and strikeouts to flag changes) showed that not all of the differences between the two labels had been flagged (FDA, 2000, 2002), so an interim label may have been issued. Only those label changes that refer to adverse reactions that occur in adults using A/P as prophylaxis are reviewed here. By 2002 a contraindication for A/P in persons with severe renal impairment (creatinine clearance <30 mL/min) appeared in the label (FDA, 2002). A/P users were also warned not to take a double dose after missing a dose. 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 ârare cases of seizures and psychotic events (such as hallucinations)â but stated that a causal relationship had not been established (FDA, 2004). Cutaneous adverse events, including rash, photosensitivity, angioedema, urticaria, and rare cases of anaphylaxis were added to this section, as were erythema multiforme and Stevens-Johnson syndrome. The 2008 label cautioned against using atovaquone with indinavir (due to a decrease in trough levels of indinavir) and advised care when starting or stopping prophylaxis with A/P in persons taking coumarin-based anticoagulants, noting that coagulation should be monitored (FDA, 2008). The Postmarketing Adverse Reactions section added blood and lymphatic system disorders (neutropenia and rarely anemia; pancytopenia in persons with severe renal impairment treated with
ATOVAQUONE/PROGUANIL 221 proguanil); immune system disorders (allergic reactions, including angioedema, urticaria, and rare cases of anaphylaxis and vasculitis); gastrointestinal disorders (stomatitis); and hepatobiliary disorders (elevated liver function tests and rare cases of hepatitis and cholestasis; a single reported case of hepatic failure requiring transplant). âRare cases of vasculitisâ was amended to âvasculitisâ; angioedema and ârare cases of anaphylaxisâ were deleted; and ârare cases of seizures and psy- chotic eventsâ was amended to delete ârare.â 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). The 2019 label noted that the proguanil component of A/P acts to inhibit parasitic dihydrofolate reduc- tase but added that pregnant women and females of reproductive potential should continue folate supplementation to prevent neural tube defects (FDA, 2019a). New data from animal studies, using doses higher than prophylaxis-equivalent doses in humans, indicated that atovaquone does not yield fetal malformations, proguanil is not associated with embryo-fetal toxicity, and the combination of atovaquone and proguanil does not yield embryo/fetal developmental effects. PHARMACOKINETICS The pharmacokinetics of A/P are well reviewed by Boggild et al. (2007) and Nixon et al. (2013). Atovaquone is a highly lipophilic compound with low a Â queous solubility; thus taking this drug with dietary fat increases its absorption. It has an elimination half-life of 2â4 days. Atovaquone is highly bound to plasma protein (>99%) and has a high volume of distribution and low clearance (Zsila and Fitos, 2010). Elimination is primarily via the liver, with very low amounts (0.6%) of drug eliminated via the kidneys. Greater than 90% of atovaquone excreted in bile is the parent drug. Proguanil is rapidly absorbed from the gastro- intestinal tract with good bioavailability. Proguanil is 75% protein bound, and it is extensively distributed in tissues. Proguanil, but not cycloguanil, is concentrated in erythrocytes, hence the five-fold difference in whole blood versus plasma con- centration. Proguanil is metabolized to cycloguanil (primarily through CYP2C19) and 4-chlorophenylbiguanide, with less than 40% excreted renally (GSK, 2015). The elimination half-life of proguanil is 15 hours in both adults and children, but it may be prolonged in individuals with a genetic polymorphism in CYP2C19 (Gillotin et al., 1999; GSK, 2015; Hussein et al., 1997; Thapar et al., 2002), which may have implications for increased toxicity. In pharmacokinetic studies conducted in healthy adults given single or Â ultiple m doses of A/P, no clinically significant interactions between atovaquone, proguanil, or its metabolite cycloguanil were observed (Gillotin et al., 1999; Â ussein et al., H 1997; Thapar et al., 2002). Pedersen et al. (2014) found that the pharmacokinetic
222 LONG-TERM HEALTH EFFECTS OF ANTIMALARIAL DRUGS properties of proguanil remained consistent even in individuals with the ultra-rapid metabolizer CYP2C19*17 single nucleotide polymorphism (SNP), indicating that the toxicity and adverse events associated with Â roguanil should be no different in p individuals with the SNP. The pharmacokinetic Â arameters of A/P are similar to p those of the drugs when used as single agents (Deye et al., 2012; Patel and Kain, 2005). The synergistic action of proguanil and atovaquone is thought to be due to its biguanide mode of action, not to the action of its metabolite(s), even in indi- viduals with CYP enzyme deficiencies who are unable to metabolize proguanil to cycloguanil (Boggild et al., 2007). ADVERSE EVENTS The following section contains a summary of the known concurrent adverse events associated with the use of A/P. 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). Many of these symptoms are avoided or relieved when A/P is taken with food (Chambers, 2003). Between 5% and 10% of individuals develop an asymptomatic elevation of hepatic transaminases (Boggild et al., 2007). There were no significant differences observed in reported adverse events in three out of six prophylaxis trials conducted in adults (Faucher et al., 2002; Shanks et al., 1998; Simons et al., 2005). Oral aphthous ulcerations are not uncommon while taking A/P, but they are rarely severe enough to warrant discontinuation (AlKadi, 2007). Discontinuation of A/P due to severe adverse events was not com- mon (Boggild et al., 2007). Tickell-Painter et al. (2017) performed a Cochrane systematic review in which adverse events were prespecified to include these disorders: psychiatric (abnormal dreams, insomnia, anxiety, depression, psychosis); nervous system (dizziness, headache); ear and labyrinth (vertigo); eye (visual impairment); gastroÂ intestinal (nausea, vomiting, abdominal pain, diarrhea, dyspepsia); and skin and subcutaneous tissues (pruritus, photosensitivity, vaginal candida). The purpose of the assessment was to summarize the efficacy and safety of mefloquine for malaria prophylaxis in adult, children, and pregnant women travelers as compared
ATOVAQUONE/PROGUANIL 223 with other antimalarials (including A/P), placebo, or no treatment. The dosages of mefloquine varied, as did the methods of collecting adverse event data. 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). In the included cohort studies, no serious adverse events were reported among A/P users. Regarding neurologic adverse events, mefloquine users were more likely to report headache than A/P users, but this finding was only statistically sig- nificant across the cohort studies (RR = 3.42, 95%CI 1.71â6.82; 8 cohort studies, 4,163 participants). Similarly, dizziness was more common in mefloquine users than among A/P users in the trial (RR = 3.99, 95%CI 2.08â7.64) and in eight cohort studies (RR = 3.83, 95%CI 2.23â6.58; 3,986 participants). 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. Consistent, larger effects were observed in the cohort studies. In addition, no A/P users reported abnormal thoughts or perceptions, as compared with 21 mefloquine users, but the differences between groups did not reach statistical significance. When mefloquine users were compared with A/P users, mefloquine users were more likely to experience nausea based on one trial (RR = 2.72, 95%CI 1.52â4.86; 976 participants) and seven cohort studies (RR = 2.50, 95%CI 1.54â4.06; 3,509 participants), but there were no statistically significant differences for vomiting, abdominal pain, or diarrhea. In contrast, the risk of mouth ulcers was higher in A/P users than in mefloquine users (effect estimates recalculated to directly compare A/P with mefloquine instead of mefloquine with A/P) in two cohort studies (RR = 8.33, 95%CI 2.70â25.0; 783 participants), but not in the single trial (RR = 0.68, 95%CI 0.33â1.43; 976 participants) that included this outcome. Other symptoms were also included when available. Based on one trial and three cohort studies, no difference between A/P and mefloquine users was found for experiencing pruritus, although the estimate was imprecise. One trial and two cohort studies found no statistically significant differences for visual impairment between mefloquine and A/P users. Another systematic review and meta-analysis was identified that included 10 randomized trials of children and adults (but excluded studies of people with comorbidities or who were pregnant or nursing) to examine the effectiveness, safety, and tolerance of A/P as a prophylactic agent against malaria (Nakato et al., 2007). Although studies examining adverse events in individuals less than 16 years of age were excluded from the committeeâs consideration, because the study groups may have contained individuals 16 years of age or older the results of this review are reported. Those taking A/P did not report adverse events more frequently than those taking placebo. Only one serious adverse event was reported in an individual taking A/P, who was hospitalized after repeated vomiting. The authors reported that there were no significant differences in adverse events between individuals
224 LONG-TERM HEALTH EFFECTS OF ANTIMALARIAL DRUGS taking two times the approved dose of A/P used for prophylaxis and individuals taking a placebo. In several of the post-cessation epidemiologic studies, includ- ing those presented in the other antimalarial drug chapters, A/P is often used as a reference group because of its strong safety and tolerability profile. Post-Cessation Adverse Events A total of 960 abstracts or article titles were identified by the literature search for A/P. After screening, 418 abstracts and titles were retained, and the full text for each was retrieved and reviewed to determine whether it met the inclusion criteria, as defined in Chapter 3. The committee reviewed each article and identified four post-cessation epidemiologic studies that included some mention of adverse events that occurred â¥28 days post-A/P-cessation (Eick-Cost et al., 2017; Schneider et al., 2013, 2014; Tan et al., 2017). These are summarized below and form the basis of the body of evidence on the persistent and latent adverse events of A/P. A table that gives a high-level comparison (study design, population, exposure groups, and outcomes examined by body system) of each of these four epidemiologic studies is presented in Appendix C. Military and Veterans Using Department of Defense (DoD) administrative databases, Eick-Cost et al. (2017) performed a retrospective cohort study among 367,840 active-duty ser- vice members who filled at least one prescription for an antimalarial drug 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 Modification (ICD-9-CM)-coded neurologic and psychiatric outcomes (adjustment disorder, 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 during concurrent use plus 365 days after the end of the prescription for mefloquine, doxycycline, and A/P. Although the authors did not report on results for the period of â¥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, âHowever, none of these analyses significantly changed the results of the study and are therefore not reportedâ (p. 161). This statement implies (but does not show directly) that findings simi- lar to those reported would be seen if the reporting period were restricted to the period relevant to the committeeâs definition of persistence (i.e., â¥28 days after cessation of exposure). The committee was unsure how to interpret the claim that different analyses did not change the results significantly (i.e., there was no infor-
ATOVAQUONE/PROGUANIL 225 mation about statistical significance, the precision of effect estimates, the number of diagnoses, etc.), but given that the authors performed sensitivity analyses, the number of methodologic strengths, including a strong measurement of relevant outcomes conducted in the target population, the committee chose to include the study, despite the ambiguity in the language. If an individual had multiple pre- scriptions 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 different antimalarial. Analyses were stratified by deployment and psychiatric history. Models were adjusted for age, sex, service, grade, and the year the prescription started; analyses of deployed service members also controlled for location and combat exposure. A/P recipients had primar- ily served in the Army (34%), many were senior enlisted officers (23%), and a majority had prescriptions filled after 2012 (55%). Among the deployed service members, fewer individuals who had received A/P reported combat exposure (21%, compared with 29% for mefloquine and 43% for doxycycline). 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. The effect estimates of neurologic and psychiatric outcomes for mefloquine and doxycycline are reported in those respective chapters. For A/P users, the highest incident rates in both deployed and nondeployed service members were for adjustment disorder (31.61 versus 13.6 per 1,000 person-years, respectively), followed by insomnia (23.21 versus 10.74 per 1,000 person-years, respectively) and anxiety disorder (14.97 versus 8.69 per 1,000 person-years, respectively). Incident depressive disorder (7.09 versus 6.86 per 1,000 person-years, respectively), convul- sions (2.31 versus 0.69 per 1,000 person-years, respectively), and hallucinations (0.58 versus 0.38 per 1,000 person-years, respectively) were also higher among the deployed group. On the other hand, the incidence rates for tinnitus (10.24 versus 11.27 per 1,000 person-years, respectively), vertigo (11.24 versus 11.42 per 1,000 person-years, respectively), suicide ideation (0.71 versus 1.47 per 1,000 person- years, respectively), and psychoses (0 versus 0.17 per 1,000 person-years, respec- tively) were higher among the nondeployed than among the deployed. Among those prescribed A/P, the incidence rate of PTSD was 6.74 per 1,000 person-years in the deployed group and 3.81 per 1,000 person-years in the nondeployed group. Adjusted incident rate ratios (IRRs) comparing mefloquine to A/P by deployment status found that among the deployed, mefloquine users were more likely to expe- rience tinnitus than A/P users (IRR = 1.81, 95%CI 1.18â2.79). When mefloquine and A/P users were compared among the nondeployed, mefloquine users had a significantly higher risk of tinnitus (IRR = 1.51, 95%CI 1.13â2.03) and PTSD (IRR = 1.83, 95%CI 1.07â3.14). No other neurologic or psychiatric outcomes were statistically significantly different between mefloquine and A/P users in either the deployed or nondeployed groups. In a second study objective, the investigators compared the risk of developing a neurologic or psychiatric outcome in mefloquine
226 LONG-TERM HEALTH EFFECTS OF ANTIMALARIAL DRUGS and doxycycline users with and without a neurologic or psychiatric diagnosis in the year prior to receiving antimalarial drugs; A/P was excluded from this analysis due to the small sample size. The committee found this study to be well designed. Important factors that increased the studyâs quality are its large sample size; the use of an administrative data source, which provides some degree of objectivity; and a careful consid- eration of potential confounding variables including demographics, psychiatric history, and the 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 â¥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 regimens. 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 medical diagnoses are likely to be more reliable than self-report for determining the outcomes, the data are dependent on the accuracy of the coding, and there was no validation of the diagnoses recorded in the administrative databases, and any 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. Given the largely null results reported for comparisons with A/P, this implies that null results would be found for the period of interest, but the data were not presented to make it pos- sible to examine this assumption directly. U.S. Peace Corps Tan et al. (2017) conducted a retrospective observational Internet-based survey of 8,931 (11% response rate) returned U.S. Peace Corps volunteers (who had served during 1995â2014) 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. The reported initial anti- malarial prophylactic prescriptions were mefloquine (n = 2,981; 59.0%), A/P (n = 183; 3.6%), chloroquine (n = 674; 13.3%), doxycycline (n = 831; 16.4%), and 386 (7.6%) âotherâ prophylactic medications. In addition to questions on malaria prophylaxis (type, regimen, duration, and adherence), the survey included ques- tions about the country of service, the type of assignment, and whether malaria Â rophylaxis was required at the assigned site. Respondents were also asked to p 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
ATOVAQUONE/PROGUANIL 227 before, during, and after Peace Corps service. In addition they were questioned about a family history of disease and psychiatric illness, any psychiatric his- tory prior to exposure, and alcohol consumption. In total, more than 40 disease outcomes were examined for associations with each antimalarial; these included derived outcomes of major depressive disorder, bipolar disorder, anxiety disorder, insomnia, psychoses, and cancers. Outcomes were grouped by system (neuroÂ psychologic, cardiac, ophthalmologic, dermatologic, reproductive, and gastro- intestinal) or class (infectious, hematologic/oncologic) and within each group several diagnoses were listed. âAny psychiatric outcomeâ included all reported psychiatric diagnoses both derived and those reported as individual diagnoses, including schizophrenia, obsessive-compulsive disorder, and âother.â Neuro- psychologic disorders were presented as a category and that separately included dementia, migraines, seizures, tinnitus, vestibular disorder, âotherâ neurologic disorder, and âanyâ neurologic disorder. The authors reported that there were no differences in the prevalence of post-service Peace Corps disease diagnoses between those who had used A/P and those who had not. The diagnoses men- tioned were those derived from reported and feared adverse events with A/P such as migraines, based on reports of headaches, fatty liver, cirrhosis, or liver failure, although the specific effect estimates were not shown. There were no statistical results presented for outcomes related to A/P exposure. 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 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. 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- reports that were provided years (range 2â20 years) after the 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 acting 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 validated against any objective information. The results presented in this study do not support the presence of persistent or latent health effectsâor incident neurologic or psychiatric effects specificallyâafter A/P cessation, but the design limitations of this study are such that any evidence provided by this study is weak.
228 LONG-TERM HEALTH EFFECTS OF ANTIMALARIAL DRUGS Travelers Schneider et al. (2013, 2014) conducted two retrospective observational Â tudies s in travelers using data from the UK-based General Practice Research Â atabaseD (GPRD)âwhich has since changed names to the Clinical Practice Research D Â atalinkâto 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). While the specific outcomes examined (Â eurologic, psychiatric, and eye disorders) in the two antimalarial drug studies n differed, the general methodology was the same. Using the GPRD, investiga- tors identified individuals who had at least one prescription for mefloquine, A/P, d Â oxycycline, 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 included specific codes indicating that the prescription was for malaria prophylaxis. The start of follow-up was the date of receipt of the first prescription for an indi- vidual. Current use was defined as between the date a prescription started and one week after the end of the time period of the drug prescription. Current exposure time was calculated differently for each antimalarial drug because the regimens for the antimalarial drugs differ. Investigators based the 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 A/P, the current exposure time (in days) was the number of tablets plus 7 days. Investigators added 90 days to each exposure time to capture events occurring during travel that came to the attention of the general practitioner after returning to the United Kingdom. Recent use included periods both relevant to the committeeâs charge (days 28â89) and time periods that the committee considered exclusionary (days 7â27). Past use started at day 91 and ended at a maximum of 540 days after the end of cur- rent exposure, reflecting a time period pertinent to the committeeâs assessment. Non-exposed people served as controls and had no antimalarial prescription dur- ing the study period or during 540 days after their pre-travel consultation, 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 their travel consultation for the non-exposed controls. 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 caseâcontrol analysis was also performed for a subset of the population in which six controls (who did not develop an outcome of interest
ATOVAQUONE/PROGUANIL 229 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 a uniform collection of exposures and outcomes that were not subject to recall bias. The nested caseâcontrol com- ponent allowed for the control of important covariates. The reliance on recorded drug prescriptions to determine exposure ensures that the assessment was applied equally to all exposure groups; however, as with any study that relies on adminis- trative databases, the prescriptions were 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 apparent differences in outcomes between the groups. However, it is unlikely that this would result in differential selection bias. Additional strengths and limitations that are study-specific are noted within each study summary. Schneider et al. (2013) estimated the incidence of anxiety, stress-related disor- ders, or psychosis (n = 952); depression (n = 739); epilepsy (n = 86); or peripheral neuropathy (n = 56) in individuals (aged â¥1 year) with a 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 prophylaxis or else no anti- malarial prescription (but who had a pre-travel consultation) (n = 41,573) between January 1, 2001, and October 1, 2009. 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. For the unexposed group, indi- viduals were excluded if there was a record of 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 or psychiatric outcomes that occurred up to 540 days following current use of A/P compared with other antimalarials and with no use of antimalarials. Although 15.3% of the population was â¤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 in individuals using A/P were higher than the comparable incidence rates for individuals using
230 LONG-TERM HEALTH EFFECTS OF ANTIMALARIAL DRUGS mefloquine but lower than incidence rates in individuals using chloroquine and/ or proguanil or who were unexposed. A nested caseâcontrol analysis was also conducted in which investigators categorized subjects into current (use of drug plus 90 days post-cessation) or past-use (91â540 days post-cessation) exposure groups and controlled for age, sex, calendar time, general practice, smoking, and body mass index (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. When considering current use (which includes a mixture of nonrelevant [during use to 27 days post-use] and relevant [day 28â90 post-use] time periods) compared with travelers who did not use any antimalarial prophylaxis and after adjustment for BMI and smoking, the odds of developing anxiety, stress-related disorders, or psychosis (OR = 0.92, 95%CI 0.72â1.18); epilepsy (OR = 1.42, 95%CI 0.59â3.42); and peripheral neuropathy (OR = 1.51, 95%CI 0.54â4.21) were no greater among current A/P users. However, current A/P users were found to have statistically significantly decreased odds of developing depression compared with those who did not use antimalarials (OR = 0.56, 95%CI 0.40â0.80). When con- sidering past exposure, the odds of developing anxiety, stress-related disorders, or psychosis were statistically significantly decreased in past users of A/P compared with those who did not use an antimalarial (OR = 0.65 95%CI 0.54â0.79). There were no statistically significant differences for depression, epilepsy, or peripheral neuropathy when examining past A/P exposure with no use of antimalarials. When anxiety, psychosis, phobia, and panic attack were analyzed as separate outcomes, compared with no antimalarial users, A/P users had statistically significantly decreased odds of developing phobia (OR = 0.64, 95%CI 0.43â0.96) and anxiety (OR = 0.66, 95%CI 0.52â0.84). However, these analyses were based on any use of A/P, and it was not stratified by current or past exposure time. This large, adequately powered study provides evidence of decreased odds of depression among current users of A/P and decreased odds of anxiety, stress- related disorders, and psychosis (combined outcome) among past users, and it found no evidence of an increase in anxiety, stress-related disorders, or psychosis (combined outcome), depression, epilepsy, or peripheral neuropathy associated with A/P use for malaria prophylaxis in travelers when assessing current use or past use and follow-up for 18 months compared with people who did not use antimalarials. The comparison group consisted of travelers as well, but they may have traveled to non-malaria-endemic areas or had unmeasured risk factors that contraindicated antimalarial prophylaxis. The 1-year medical record history used to assess psychiatric conditions is unlikely to reflect a complete psychiatric his- tory. 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 A/P use for malaria prophylaxis in travelers aged â¥1 year when assessing current use and 18 months following current use.
ATOVAQUONE/PROGUANIL 231 Using the same design and administrative database as described by Â chneider S et al. (2013), Schneider et al. (2014) examined the incidence of clinical eye disorders (n = 652) in travelers (aged â¥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, lens, uvea, iris, retina, or other parts of the eye, or glaucoma). Because only 20 of the total 652 eye disorders occurred among people â¤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 â¤17 years. Among A/P users, there were a total of 244 incident eye disorders identified (54 occurred within 90 days of finishing the prescription, and 190 occurred between 91 and 540 days after 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-ophthalmalogic disorders (the latter including optic neuritis, diplopia, trigeminal neuralgia, and other conditions). Incidence rates were estimated for each eye disorder category by antimalarial group, but no comparisons between groups were made. A nested caseâcontrol 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 1.03â1.52). However, when A/P use was stratified by current (defined as use of drug plus 90 days post-cessation) and past use (91â540 days post-cessation) and compared with the nonusers, for current users there were not statistically significantly increased odds (OR = 1.04, 95%CI 0.75â1.43), whereas past users had statistically significantly increased odds (OR = 1.34, 95%CI 1.08â1.66), suggesting that the overall finding was driven by the association with past exposure. When each of the individual eye disor- der categories was examined, both cataracts (OR = 2.00, 95%CI 1.3â3.08) and retinal disorders (OR = 1.83, 95%CI 1.07â3.13) showed statistically significantly increased odds in relation to A/P use (these results were not stratified by current or past timing of exposure). The strengths and limitations of this study mirror those discussed in Schneider et al. (2013). Although âcurrent useâ likely captured some events within the 28-day post-cessation window, it is unlikely to have resulted in selection bias. The finding of increased risk of cataracts and retinal disorders with A/P use was unexpected and would require confirmatory evidence. Other risk factors for retinal disorders, such as a family history of retinal disorders, were not included in the analysis and
232 LONG-TERM HEALTH EFFECTS OF ANTIMALARIAL DRUGS may have differed between the groups. Overall, the study suggests an increased risk of developing eye disorders in past users and an increased risk of developing cataracts and retinal disorders for users of A/P relative to nonusers of antimalarials. OTHER IDENTIFIED STUDIES OF A/P PROPHYLAXIS IN HUMAN POPULATIONS The committee also reviewed several studies of A/P use in service members from the United States (Saunders et al., 2015), Colombia (Soto et al., 2006), the United Kingdom (Tuck and Williams, 2016), Sweden (Andersson et al., 2008), and Canada (Paul et al., 2003). However, these studies either did not follow military cohorts after the A/P prophylaxis was completed or did not report on adverse events that occurred post-A/P-cessation; therefore, they were not further considered. A number of studies were designed to examine the safety or tolerability of A/P when used in nonimmune travelers, but they did not report on adverse events or other outcomes occurring at least 28 days post-cessation of A/P or distinguish the timing of those events (within or after 28 days post-cessation) (HÃ¸gh et al., 2000; Kato et al., 2013; Laverone et al., 2006; Overbosch, 2003; Overbosch et al., 2001; Schlagenhauf et al., 2003, 2009; Sharafeldin et al., 2010; van Genderen et al., 2007; van Riemsdijk et al., 2002). Similarly, several studies conducted in healthy volunteers (Deye et al., 2012; Gillotin et al., 1999; Sukwa et al., 1999; Thapar et al., 2002), endemic populations (Berman et al., 2001; Shanks et al., 1998), migrants (Ling et al., 2002; van Vugt et al., 1999), and individuals with occupation-related exposure to malaria prophylaxis (Cunningham et al., 2014; Landman et al., 2015; Nicosia et al., 2008) did not report any adverse events occurring beyond 28 days post-cessation of A/P. Simons et al. (2005) conducted a study in healthy volunteers under aircraft pressure to evaluate the impact of A/P on in-flight performance. Individuals were split into two groups in a crossover study design, resulting in different lengths of follow-up after the use of A/P; however, reported adverse events were not reported individually for each group (one group was followed for more than 28 days post-cessation of A/P), making it impossible to distinguish between adverse events that occurred Ë28 days post-cessation or â¥28 days post-cessation, and, as a result, this study was not further considered. 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 com- mittee reviewed three case reports, totaling three patients, which reported adverse events that persisted for at least 28 days following A/P cessation. There was one case of phototoxicity after sun exposure while taking A/P, and this condition per-
ATOVAQUONE/PROGUANIL 233 sisted for âseveral monthsâ (Amelot et al., 2014). A case of vanishing bile duct syndrome was diagnosed in a male traveler who presented with jaundice, Â ruritus, p lethargy, dark urine, and pale stool (Abugroun et al., 2019). A liver biopsy indi- cated mild interface hepatitis and marked bilorubinostasis. The traveler recovered but then was re-admitted to the hospital 2 months later, and a repeat liver biopsy showed diffuse ductopenia, diagnostic of vanishing bile duct syndrome. Over 18 months of follow-up, his symptoms and laboratory values improved. Finally, T Â erziroli Beretta-Piccoli et al. (2017) reported a case of A/P-induced autoimmune- like hepatitis in a traveler who presented with jaundice, fatigue, and dark urine with elevated laboratory values and a liver biopsy significant for portal inflam- mation with plasma cell rich interface activity, severe zone 3 necrosis, but no significant fibrosis. He was treated with prednisone, and at 6-month follow-up his laboratory tests were normal, but a repeat liver biopsy was still abnormal. At 1-year follow-up, the liver biopsy was normal. These three cases suggest that though A/P is generally well tolerated, cutaneous and liver-related adverse events should be clinically monitored. Selected Subpopulations In the course of its review of the literature on A/P, the committee identified and reviewed available studies that reported results stratified by demographic, medi- cal, or behavioral factors to assess whether the risk for adverse events when using A/P 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 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. The following risk groups were specifically considered: pregnant women and those with comorbid diseases or disorders. Pregnancy Available data from the published literature and postmarketing experience with use of A/P in pregnant women are insufficient to identify a drug-associated risk for major birth defects, miscarriage, or adverse maternal or fetal outcomes. Postmarketing surveillance (Mayer et al., 2018) and registry-based cohort studies (Duffy and Fried, 2005; Kaser et al., 2015; McGready et al., 2003) have failed to find a consistent, significant association between poor birth outcomes and the use of A/P taken at any point during pregnancy or breastfeeding. For example, a large registry-based cohort study conducted in Denmark found no significant association between exposure to A/P in early pregnancy and the risk of any major birth defect (Pasternak and Hviid, 2011). A systematic review of A/P for the prevention and
234 LONG-TERM HEALTH EFFECTS OF ANTIMALARIAL DRUGS treatment of malaria in pregnancy showed that outcomes following A/P exposure during pregnancy are similar to the expected rates in similar populations Â ndrejko A et al., 2019). An analysis of birth outcomes following accidental exposures to A/P during pregnancy recorded in the A/P-exposed pregnancies database (a pas- sive reporting system) found no concerning signals of poor pregnancy outcomes, although there was a possible higher rate of congenital anomalies with no apparent pattern. There are data to suggest that adjusting the dose of A/P during pregnancy may be warranted because blood plasma levels of the drug are lower in pregnant women (Davis et al., 2010; Nosten et al., 2006) and proguanil monotherapy is considered safe during pregnancy (Mayer et al., 2018). Because of insufficient data on its safety in pregnancy, the Centers for Disease Control and Prevention does not recommend the use of A/P for the prevention or treatment of malaria during pregnancy (CDC, 2018, 2019). Comorbid Diseases Many travelers have comorbid medical conditions that require them to take medication. In these individuals, there is the potential for drugâdrug interactions with prophylactic antimalarial drugs, which may result in harmful consequences. One study examined A/P use in individuals with renal impairment and found no issues with the use of A/P, but it noted that dosage adjustments may be needed for proguanil because of the altered pharmacokinetics (Amet et al., 2013). BIOLOGIC PLAUSIBILITY Whole animal studies of A/P conducted in mice, rats, and dogs found toxicity to be no greater than that observed for either drug alone (FDA, 2019a). These studies were primarily observational and examined immediate and concurrent effects; they were not designed to investigate possible mechanisms of action. The experimental animal studies administered A/P at the equivalent of treatment doses (which are about four times higher than the prophylactic dose) but did not conduct long-term post-administration follow-up (instead it was limited to hours to days), as is stan- dard procedure for preclinical toxicology studies (NRC, 2006). The combination of A/P was not embryotoxic at clinically relevant concentrations (FDA, 2019a). Investigators also found that there was no accumulation of atovaquone within human cells, making it less likely for adverse events to occur. However, atovaquone may reduce the elimination of proguanil in extensive metabolizer phenotypes, so that in these individuals, proguanil concentrations may be elevated (Thapar et al., 2002). 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
ATOVAQUONE/PROGUANIL 235 suggesting plausible biologic mechanisms underlying persistent or latent effects of malaria prophylaxis in humans. Further studies would be needed to ascertain whether there are persistent cellular effects associated with the use of A/P for malaria prophylaxis. SYNTHESIS AND CONCLUSIONS A/P as a combination drug has been approved for use as a prophylactic drug for malaria since 2000. It is generally well tolerated and has often been used as a comparator in studies of efficacy and tolerability of other antimalarial drugs because it is less likely to be discontinued due to adverse events than other pro- phylactic drugs for malaria, such as mefloquine (Kain et al., 2001; Overbosch et al., 2001; Tickell-Painter et al., 2017). 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. Four epidemiologic studies were identified that reported on adverse events at least 28 days post-A/P-cessation (Eick-Cost et al., 2017; Schneider et al., 2013, 2014; Tan et al., 2017). These studies considered different populationsâmembers of the U.S. military (Eick-Cost et al., 2017); returned U.S. Peace Corps volun- teers (Tan et al., 2017); and travelers (Schneider et al., 2013, 2014)âand they considered different health outcomes, with the studiesâ varying definitions making a synthesis of the findings challenging. For example, three of the post-cessation epidemiologic studies for A/P collected and reported information that could be categorized as psychiatric outcomes; however, these ranged from nonspecific broad categories, such as âneuropsychologic,â to specific symptoms such as sleep disturbances and anxiety, and clinical diagnoses such as PTSD, depressive disor- der, and psychosis, posing a challenge to the committeeâs ability to make an inte- grated assessment. Given the inherently imperfect information generated by any one study, it would be desirable to have similar studies to assess the consistency of the findings, but the diversity of the methods used within the included epide- miologic studies makes it very difficult to combine information across Â tudies s with confidence. Even when pertinent data appeared to have been collected to meet the committeeâs inclusion criteria of reporting on an adverse event or health outcome (or if there were none reported) 28 days post-drug-cessation, not all of the information relevant to the committeeâs charge was presented because it was not a main objective or a focus of the study (e.g., studies that were designed to examine long-term efficacy against clinical malaria). 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 A/P cessation, but the only outcomes reported were on incident cases of malaria or generic statements about all adverse events having resolved. Another limitation across the included
236 LONG-TERM HEALTH EFFECTS OF ANTIMALARIAL DRUGS studies was that it was not always possible to identify whether concurrent adverse events persisted beyond the time of drug cessation, thus the studies did not all contribute equally to the ultimate conclusion of the association between A/P and persistent or latent adverse events of a given health outcome. In general, the reviewed epidemiologic studies were not designed to examine the persistence of adverse events in individuals, but rather they collected information on whether adverse events were detected at some time period at least 28 days after cessation of A/P. To avoid repetition for each outcome category, a short summary of the attributes of each study that was considered to be contributory to the evidence base is presented first. The evidence summaries for each outcome category refer back to these short assessment summaries. For each health outcome category, supporting information from FDA, known concurrent adverse events, case studies, information on selected subpopulations, and experimental animal and in vitro studies are first summarized before the evi- dence from post-cessation epidemiologic studies is described. While the charge to the committee was to address persistent or latent adverse events, the occurrence of concurrent adverse events enhances the likelihood that problems may persist beyond the period after cessation of drug use. 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. Epidemiologic Studies Presenting Contributory Evidence Eick-Cost et al. (2017) used DoD administrative databases to perform a large retrospective cohort study of 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 a careful consideration of potential confounders including demographics, psychiatric history, and the 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 â¥28 days post-cessation, the study pro- vides 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 the post-cessation period. Whereas medical diagnoses are likely to be more reliable
ATOVAQUONE/PROGUANIL 237 for the outcomes of 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 about when the index trauma occurred. 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 â¥1 year using A/P compared with other antimalarial drugs for malaria prophylaxis relative to travelers who did not use an antimalarial. While the specific outcomes examined differed by study, the general design and methodology were the same. The use of data from the GPRD (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 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; how- ever, it is unlikely that this would result in differential selection bias. DiagÂ oses n were defined a priori, which excluded other outcomes, including the potential to identify rare outcomes. The antimalarial-exposed populations were large, an appropriate comparison group of travelers not using a form of malaria prophylaxis was included, and the 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) and 91â540 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 caseâcontrol component that allowed for the 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. Although the total number of partici- pants was large, only a small proportion (n = 183; 3.6%) used A/P. A number of important covariates, such as psychiatric history and alcohol use, were collected, but the study had several methodologic limitations. These limitations included the study design itself (self-report, Internet-based survey), an exposure characteriza- tion that was based on self-report (which introduces several potential biases such as recall bias, sampling bias, and confounding), the outcome assessment (based on self-report of health providerâdiagnosed conditions up to 20 years post-service), the use of mixed comparison groups, a lack of detail regarding the analysis meth- ods, and a poor response rate (11%, which likely introduces selection bias). The evidence generated by this study was thus considered to only weakly contribute to the inferences concerning the relationship between A/P and persistent or latent adverse events or disorders.
238 LONG-TERM HEALTH EFFECTS OF ANTIMALARIAL DRUGS Neurologic Disorders The FDA package insert listed rare cases of seizures in the Postmarketing Adverse Reactions section but stated that a causal relationship had not been established; there is no other mention of neurologic disorders. A recognized con- current adverse neurologic event associated with A/P use has been headache, but in a Cochrane systematic review, among the eight included cohort studies, A/P users were statistically significantly less likely to report headache than mefloquine users. Similarly, dizziness was statistically significantly more common in meflo- quine users than in A/P users in one trial and eight cohort studies. No persistent or latent neurologic symptoms or conditions were identified in the case reports. No experimental animal or human cell culture studies were identified that exam- ined the biologic mechanisms by which A/P might affect the central or peripheral nervous system. Eick-Cost et al. (2017) examined neurologic outcomes of tinnitus, vertigo, convulsions, and confusion. The incidence rates of tinnitus and vertigo were higher among the nondeployed than the deployed. Adjusted IRRs comparing mefloquine with A/P by deployment status found that among both the deployed and nonde- ployed, mefloquine users were statistically significantly more likely to experience tinnitus than A/P users. No other statistically significant differences were found between mefloquine and A/P users for vertigo, convulsions, or confusion in either the deployed or nondeployed groups. This study provides some evidence against the presence of persistent or latent adverse events of tinnitus, vertigo, convulsions, and confusion. Using the UK GPRD, Schneider et al. (2013) examined the association (in individuals aged â¥1 year) between A/P exposure (current and past) and an incident diagnosis of epilepsy and peripheral neuropathy in comparison with nonusers of antimalarials. In this large study, the authors found no statistically significant difference in the risk of an incident diagnosis of epilepsy or peripheral neuropathy for current or past use of A/P compared with individuals who did not use any antimalarial. This high-quality study provides some evidence against the presence of the persistent or latent neurologic adverse events of incident epilepsy and peripheral neuropathy. Tan et al. (2017) provide weak supportive evidence in their findings of no differences in the prevalence of any self-reported neurologic disease or symptom diagnoses for individuals who used A/P compared with those who did not. Based on the available evidence, the committee concludes that there is insufficient or inadequate evidence of an association between the use of ato- Â 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.
ATOVAQUONE/PROGUANIL 239 Psychiatric Disorders Although the FDA label states that seizures and psychotic events (such as hallucinations) have been observed, it also states that a causal relationship has not been established (FDA, 2019a). 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 sig- nificantly more likely than A/P users to report the psychologic adverse events of abnormal dreams, insomnia, anxiety, and depressed mood in one trial, and con- sistent, larger effects were observed in the included cohort studies. In addition, no A/P users reported abnormal thoughts or perceptions compared with 21 mefloquine users who did, but the differences between groups did not reach statistical signifi- cance (Tickell-Painter et al., 2017). No persistent or latent psychiatric symptoms or conditions were identified in the case reports. No experimental animal or human cell culture studies were identified that examined biologic mechanisms for A/P and psychiatric outcomes. Three epidemiologic studies examining psychiatric effects met the com- mitteeâs inclusion criteria. Two were well designed (Eick-Cost et al., 2017; Schneider et al., 2013), but the third was limited in that statements were made concerning âneuropsychologic outcomesâ as a whole but it did not distinguish specific psychiatric outcomes (Tan et al., 2017). Eick-Cost et al. (2017) examined more Â sychiatric outcomes than Schneider et al. (2013), although some of the p outcomes were similar. Eick-Cost et al. (2017) examined outcomes of adjustment disorder, anxiety disorder, depressive disorder, PTSD, psychoses, suicide, suicide ideation, hallucinations, paranoia, and insomnia. Schneider et al. (2013) examined anxiety, stress-related disorders, and psychosis (as a group and individually) and depression. Eick-Cost et al. (2017) found that with the exception of suicidal ideation and psychosis, adjusted incident rates for all psychiatric outcomes were higher among the deployed than among the nondeployed for those prescribed A/P. Although incident diagnoses of PTSD were reported for both deployed and nondeployed A/P users, comparisons of mefloquine users and A/P users stratified by deployment status found that none of the psychiatric outcomes were statistically significantly different among the deployed group. Among the nondeployed, only PTSD showed a statistically significantly decreased risk for A/P users compared with mefloquine users. Using the UK GPRD, Schneider et al. (2013) examined the relationship (in individuals aged â¥1 year) between A/P exposure (current or past) and incident anxiety, stress-related disorders, and psychosis (as a group) and depression in com- parison with nonusers of antimalarials. For current use (which includes a mixture of irrelevant [during use to 27 days post use] and relevant [days 28â90 post use] time periods), the odds of developing anxiety, stress-related disorders, or psychosis were not statistically significantly different between A/P users and nonusers, but the odds were statistically significantly decreased for past A/P users compared with
240 LONG-TERM HEALTH EFFECTS OF ANTIMALARIAL DRUGS nonusers. For depression, current A/P usersâbut not past A/P usersâwere found to have statistically significantly decreased odds of developing depression from the comparison group that did not use antimalarials. When restricting to past exposure (91â540 days post-use), the odds of developing anxiety, stress-related disorders, or psychosis were statistically significantly decreased for past users of A/P compared with those who did not use an antimalarial, but there was no difference for depres- sion. When anxiety, psychosis, phobia, and panic attack were analyzed as separate outcomes, compared with nonusers of antimalarials, A/P users (combined current and past use) had statistically significantly decreased odds of developing phobia and anxiety. Both Eick-Cost et al. (2017) and Schneider et al. (2013) provide some evidence against the presence of persistent or latent psychiatric conditions in the specific outcomes examined in individuals using A/P for malaria prophylaxis. Based on the available evidence, the committee concludes that there is insuf- ficient or inadequate evidence of an association between the use of atovaquone/Â proguanil for malaria prophylaxis and persistent or latent psychiatric events. C Â urrent evidence does not suggest further study of such an association is war- ranted, given the lack of evidence regarding biologic plausibility, adverse events associated with concurrent use, or findings from the existing epidemiologic studies. Gastrointestinal Disorders The 2019 FDA package insert lists diarrhea and oral ulcers as common con- current adverse events associated with the use of A/P. The package insert also notes that cases of hepatitis and one account of hepatic failure requiring liver transplant have been reported with the prophylactic use of A/P. In a systematic review of concurrent adverse events in short-term travelers, A/P users were statistically significantly less likely to experience concurrent nausea than mefloquine users and statistically significantly more likely to report mouth ulcers than mefloquine users. There were no statistically significant differences in vomiting, abdominal pain, or diarrhea. One case report was identified that indicated that the use of A/P may have resulted in vanishing bile duct syndrome and the subsequent develop- ment of mild interface hepatitis and marked bilorubinostasis. A second case report described auto-immune-like hepatitis in an individual using A/P for malaria pro- phylaxis. Experimental animal and human cell culture studies that used A/P were also examined for evidence of mechanisms that could plausibly support adverse events, and the committee was unable to identify any such mechanisms that would support persistent or latent gastrointestinal adverse events. Tan et al. (2017) was the only epidemiologic study identified that examined gastrointestinal outcomes and the use of A/P. The included conditions were Â irrhosis, c esophageal ulceration, fatty liver, liver failure, peptic ulcer, and âanyâ liver dysfunc- tion. The study found no association between A/P users and any of these conditions compared with people who did not use A/P, but specific frequencies or effect esti- mates were not reported; the limitations of this study are described above.
ATOVAQUONE/PROGUANIL 241 Based on the available evidence, the committee concludes that there is insuf- ficient or inadequate evidence of an association between the use of atovaquone/ proguanil 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 concur- rent use, or findings from the existing epidemiologic studies. Eye Disorders The FDA label is silent on eye disorders, and no case studies of latent or per- sistent 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). No experimental animal or human cell culture studies were identified that examined biologic mechanisms for A/P and eye disorders. Using the UK GPRD, Schneider et al. (2014) examined the relationship (in individuals aged â¥1 year) between A/P exposure (current and past) and incident eye disorders affecting the cornea, uvea, lens, iris, retina, or other parts of the eye relative to nonusers. The primary finding was a statistically significant increase in the odds of any eye disorder among users of A/P relative to nonusers, which appeared to be driven by past use rather than current use, suggesting a latent adverse event. Further analysis of specific eye disorders revealed a statistically significant increased risk of cataracts and retinal disorders in users of A/P relative to nonusers (these results were not stratified by current or past timing of expo- sure). This single high-quality study provides some evidence for the presence of persistent, possibly latent, eye disorders, specifically cataract and retinal disorders; however, because there is only a single study, the evidence for eye disorders asso- ciated with use of A/P must be considered insufficient. Given its limitations, Tan et al. (2017) could only provide supportive evidence, and it reported no differences in any ophthalmologic conditions (macular degeneration, retinopathy, âanyâ ophthal- mologic disorder) for individuals who used A/P compared with those who did not. Based on the available evidence, the committee concludes that there is insuf- ficient or inadequate evidence of an association between the use of atovaquone/ proguanil for malaria prophylaxis and persistent or latent eye disorders. Current evidence suggests further study of such an association is warranted, given the evi- dence regarding biologic plausibility, adverse events associated with concurrent use, or findings from the existing epidemiologic studies. Cardiovascular Disorders The FDA label and package insert do not list any cardiovascular adverse events associated with the use of A/P. The label cautions that the concomitant use
242 LONG-TERM HEALTH EFFECTS OF ANTIMALARIAL DRUGS of A/P with warfarin and other coumarin-based anticoagulants can increase their anticoagulant effects, but no evidence for concurrent or persistent adverse blood or cardiovascular outcomes was found in any of the literature reviewed on A/P. The Cochrane review examining concurrent adverse events while using antimalarials in short-term travelers did not examine cardiovascular disorders (Tickell-Painter et al., 2017). The committee did not identify any case reports that followed an individual for â¥28 days post-A/P-cessation that reported cardiovascular adverse events. Tan et al. (2017) was the only post-cessation epidemiologic study that exam- ined cardiovascular events (arrhythmia, congestive heart failure, myocardial infarction, and âanyâ cardiac disorder), but no association was found between the use of A/P and any of the cardiovascular outcomes. Based on the available evidence, the committee concludes that there is insuf- ficient or inadequate evidence of an association between the use of atovaquone/ proguanil for malaria prophylaxis and persistent or latent cardiovascular events. Current evidence does not suggest further study of such an association is war- ranted, 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) reported on associations between A/P use and other outcomes or disorders. In their survey of returned Peace Corps volunteers, Tan et al. (2017) reported no differences in any disease or symptom diagnoses for dermatologic, infectious, or cancer outcomes between individuals who used A/P and those who did not, but no effect estimates were reported for any of these outcomes. REFERENCES Abugroun, A., I. Colina Garcia, F. Ahmed, S. Potts, and M. Flicker. 2019. The first report of a Â tovaquone/proguanil-induced vanishing bile duct syndrome: Case report and mini-review. Travel Med Infect Dis, June 22 [Epub ahead of print]. AlKadi, H. O. 2007. Antimalarial drug toxicity: A review. Chemotherapy 53(6):385-391. Amelot, A., J. Dupouy-Camet, and M. Jeanmougin. 2014. Phototoxic reaction associated with Â alarone (atovaquone/proguanil) antimalarial prophylaxis. J Dermatol 41(4):346-348. m Amet, S., S. Zimner-Rapuch, V. Launay-Vacher, N. Janus, and G. Deray. 2013. Malaria prophylaxis in patients with renal impairment: A review. Drug Saf 36(2):83-91. Andersson, H., H. H. Askling, B. Falck, and L. Rombo. 2008. Well-tolerated chemoprophylaxis uni- formly prevented Swedish soldiers from Plasmodium falciparum malaria in Liberia, 2004-2006. Mil Med 173(12):1194-1198. Andrejko, K. L., R. C. Mayer, S. Kovacs, E. Slutsker, E. Bartlett, K. R. Tan, and J. R. Gutman. 2019. The safety of atovaquone-proguanil for the prevention and treatment of malaria in pregnancy: A systematic review. Travel Med Infect Dis 27:20-26.
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