National Academies Press: OpenBook
« Previous: 8 Primaquine
Suggested Citation:"9 Chloroquine." National Academies of Sciences, Engineering, and Medicine. 2020. Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis. Washington, DC: The National Academies Press. doi: 10.17226/25688.
×
Page 323
Suggested Citation:"9 Chloroquine." National Academies of Sciences, Engineering, and Medicine. 2020. Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis. Washington, DC: The National Academies Press. doi: 10.17226/25688.
×
Page 324
Suggested Citation:"9 Chloroquine." National Academies of Sciences, Engineering, and Medicine. 2020. Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis. Washington, DC: The National Academies Press. doi: 10.17226/25688.
×
Page 325
Suggested Citation:"9 Chloroquine." National Academies of Sciences, Engineering, and Medicine. 2020. Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis. Washington, DC: The National Academies Press. doi: 10.17226/25688.
×
Page 326
Suggested Citation:"9 Chloroquine." National Academies of Sciences, Engineering, and Medicine. 2020. Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis. Washington, DC: The National Academies Press. doi: 10.17226/25688.
×
Page 327
Suggested Citation:"9 Chloroquine." National Academies of Sciences, Engineering, and Medicine. 2020. Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis. Washington, DC: The National Academies Press. doi: 10.17226/25688.
×
Page 328
Suggested Citation:"9 Chloroquine." National Academies of Sciences, Engineering, and Medicine. 2020. Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis. Washington, DC: The National Academies Press. doi: 10.17226/25688.
×
Page 329
Suggested Citation:"9 Chloroquine." National Academies of Sciences, Engineering, and Medicine. 2020. Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis. Washington, DC: The National Academies Press. doi: 10.17226/25688.
×
Page 330
Suggested Citation:"9 Chloroquine." National Academies of Sciences, Engineering, and Medicine. 2020. Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis. Washington, DC: The National Academies Press. doi: 10.17226/25688.
×
Page 331
Suggested Citation:"9 Chloroquine." National Academies of Sciences, Engineering, and Medicine. 2020. Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis. Washington, DC: The National Academies Press. doi: 10.17226/25688.
×
Page 332
Suggested Citation:"9 Chloroquine." National Academies of Sciences, Engineering, and Medicine. 2020. Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis. Washington, DC: The National Academies Press. doi: 10.17226/25688.
×
Page 333
Suggested Citation:"9 Chloroquine." National Academies of Sciences, Engineering, and Medicine. 2020. Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis. Washington, DC: The National Academies Press. doi: 10.17226/25688.
×
Page 334
Suggested Citation:"9 Chloroquine." National Academies of Sciences, Engineering, and Medicine. 2020. Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis. Washington, DC: The National Academies Press. doi: 10.17226/25688.
×
Page 335
Suggested Citation:"9 Chloroquine." National Academies of Sciences, Engineering, and Medicine. 2020. Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis. Washington, DC: The National Academies Press. doi: 10.17226/25688.
×
Page 336
Suggested Citation:"9 Chloroquine." National Academies of Sciences, Engineering, and Medicine. 2020. Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis. Washington, DC: The National Academies Press. doi: 10.17226/25688.
×
Page 337
Suggested Citation:"9 Chloroquine." National Academies of Sciences, Engineering, and Medicine. 2020. Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis. Washington, DC: The National Academies Press. doi: 10.17226/25688.
×
Page 338
Suggested Citation:"9 Chloroquine." National Academies of Sciences, Engineering, and Medicine. 2020. Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis. Washington, DC: The National Academies Press. doi: 10.17226/25688.
×
Page 339
Suggested Citation:"9 Chloroquine." National Academies of Sciences, Engineering, and Medicine. 2020. Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis. Washington, DC: The National Academies Press. doi: 10.17226/25688.
×
Page 340
Suggested Citation:"9 Chloroquine." National Academies of Sciences, Engineering, and Medicine. 2020. Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis. Washington, DC: The National Academies Press. doi: 10.17226/25688.
×
Page 341
Suggested Citation:"9 Chloroquine." National Academies of Sciences, Engineering, and Medicine. 2020. Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis. Washington, DC: The National Academies Press. doi: 10.17226/25688.
×
Page 342
Suggested Citation:"9 Chloroquine." National Academies of Sciences, Engineering, and Medicine. 2020. Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis. Washington, DC: The National Academies Press. doi: 10.17226/25688.
×
Page 343
Suggested Citation:"9 Chloroquine." National Academies of Sciences, Engineering, and Medicine. 2020. Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis. Washington, DC: The National Academies Press. doi: 10.17226/25688.
×
Page 344
Suggested Citation:"9 Chloroquine." National Academies of Sciences, Engineering, and Medicine. 2020. Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis. Washington, DC: The National Academies Press. doi: 10.17226/25688.
×
Page 345
Suggested Citation:"9 Chloroquine." National Academies of Sciences, Engineering, and Medicine. 2020. Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis. Washington, DC: The National Academies Press. doi: 10.17226/25688.
×
Page 346
Suggested Citation:"9 Chloroquine." National Academies of Sciences, Engineering, and Medicine. 2020. Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis. Washington, DC: The National Academies Press. doi: 10.17226/25688.
×
Page 347
Suggested Citation:"9 Chloroquine." National Academies of Sciences, Engineering, and Medicine. 2020. Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis. Washington, DC: The National Academies Press. doi: 10.17226/25688.
×
Page 348
Suggested Citation:"9 Chloroquine." National Academies of Sciences, Engineering, and Medicine. 2020. Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis. Washington, DC: The National Academies Press. doi: 10.17226/25688.
×
Page 349
Suggested Citation:"9 Chloroquine." National Academies of Sciences, Engineering, and Medicine. 2020. Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis. Washington, DC: The National Academies Press. doi: 10.17226/25688.
×
Page 350
Suggested Citation:"9 Chloroquine." National Academies of Sciences, Engineering, and Medicine. 2020. Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis. Washington, DC: The National Academies Press. doi: 10.17226/25688.
×
Page 351
Suggested Citation:"9 Chloroquine." National Academies of Sciences, Engineering, and Medicine. 2020. Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis. Washington, DC: The National Academies Press. doi: 10.17226/25688.
×
Page 352
Suggested Citation:"9 Chloroquine." National Academies of Sciences, Engineering, and Medicine. 2020. Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis. Washington, DC: The National Academies Press. doi: 10.17226/25688.
×
Page 353
Suggested Citation:"9 Chloroquine." National Academies of Sciences, Engineering, and Medicine. 2020. Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis. Washington, DC: The National Academies Press. doi: 10.17226/25688.
×
Page 354

Below is the uncorrected machine-read text of this chapter, intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text of each book. Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.

9 Chloroquine Chloroquine is a 4-aminoquinoline synthetic derivative of quinine, and it displays increased tolerability and lower toxicity in trials comparing it with qui- nine (Berberian, 1947). Chloroquine was patented in the United States in 1941 by the Winthrop Company, a cartel partner of the IG Farbenindustrie, but its drug development was not immediately pursued (Kitchen et al., 2006). Chloroquine was synthesized in the United States during World War II by the National Research Council’s malaria chemotherapy research program in cooperation with multiple pharmaceutical companies, and it was tested among Army engineers on the Bataan Peninsula shortly before the war ended (Maier, 1948). In 1949 chloroquine phos- phate was approved by the Food and Drug Administration (FDA) under the trade name Aralen®. Its broad use among U.S. service members began in Korea in 1950 (Brundage, 2003; Kitchen et al., 2006), and chloroquine was commonly given in combination with primaquine for presumptive anti-relapse therapy (PART) during service members’ return trip to the United States following deployment (Kitchen et al., 2006). The once-weekly dosing regimen of chloroquine for malaria prophy- laxis consists of one 500 mg salt (300 mg base) tablet, which made it ideal for use in resource-limited settings such as those encountered in the military. Chloroquine was used extensively around the world until chloroquine-resistant P. falciparum was first reported in the late 1950s. The declining efficacy of chloroquine for the prevention of clinical malaria resulted in a decrease in its use for malaria prophy- laxis for several decades. Presently, chloroquine-resistant parasites can be found in almost all areas where P. falciparum is transmitted (Schlagenhauf et al., 2019). Researchers began investigating the use of chloroquine in combination with other drugs following the emergence of chloroquine-resistant parasites and iden- tified two combinations that have been widely used for malaria prophylaxis and 323

324 LONG-TERM HEALTH EFFECTS OF ANTIMALARIAL DRUGS PART. The combination of chloroquine and primaquine (known as the “C-P pill”) was given to troops returning home from Korea as well as given for standard prophylaxis for deployed service members during the Vietnam War (Brundage, 2003; Kitchen et al., 2006). Chloroquine and proguanil (chlorproguanil) has been used by foreign militaries and is approved for use in other countries (Henderson et al., 1986; Peragallo et al., 1999; Public Health England, 2018); however, the combination is not approved for use in the United States, and the committee found no indication that chlorproguanil was ever used by American service members for malaria prophylaxis. Because it is not possible to distinguish between adverse events that might result from the use of individual drugs when administered as part of a combination and adverse events that result from interactions between drugs when ingested simultaneously, the committee eliminated from further con- sideration any studies examining adverse events associated with the concurrent use of chloroquine and any other antimalarial drug (e.g., proguanil, primaquine) in its assessment of persistent and latent adverse events associated with the use of chloroquine for malaria prophylaxis. Chloroquine (and hydroxychloroquine) is used to treat diseases other than malaria, specifically rheumatoid arthritis and systemic lupus erythematosus. Seri- ous adverse events (e.g., retinopathy, macular degeneration) have been reported in people using chloroquine for the treatment of rheumatoid arthritis and systemic lupus erythematosus; however, the chloroquine regimen for treating these diseases is 250 mg per day, a much higher dose than the once-weekly 500 mg dosing regi- men used for malaria prophylaxis (Cabral et al., 2019). The result of the dosing regimen for rheumatoid arthritis and systemic lupus erythematosus is a higher cumulative dose than experienced by individuals using chloroquine for malaria prophylaxis, and the higher cumulative dose is associated with a greater severity of adverse events. The literature indicates that if an individual uses chloroquine on a long-term basis (i.e., for 5–6 years) and takes in a cumulative dose >100 g, it is possible that more severe adverse events may occur. However, the use of chloroquine for malaria prophylaxis over several years is atypical in military and veteran populations; thus, the literature examining adverse events associated with the use of chloroquine over the course of several years or as treatment of other disorders was excluded. The remainder of this chapter follows the same structure of the other anti­ malarial drug chapters, beginning with a discussion of the changes that have been made to the chloroquine package insert since 1990, with a particular emphasis on the Contraindications, Warnings, and Precautions sections. This is followed by a brief overview of the pharmacokinetic properties of chloroquine. The majority of the chapter is focused on the adverse events associated with chloroquine’s use for malaria prophylaxis, beginning with a summary of the known concurrent adverse events associated with its use when used at the dose and interval indicated for malaria prophylaxis in the package insert. Next, the three post-cessation epidemio- logic studies that met the committee’s inclusion criteria and provided information

CHLOROQUINE 325 on persistent health outcomes are summarized and assessed. These are ordered by population: military and veterans, U.S. Peace Corps, and research volunteers. A table that gives a high-level comparison of the three epidemiologic studies that examined the use of chloroquine and that met the committee’s inclusion criteria is presented in Appendix C. Supplemental, supporting evidence is then presented, including other identified studies of health outcomes in populations that used chloroquine for malaria prophylaxis but that did not meet the committee’s inclusion criteria; case reports of persistent or latent adverse events; and information on adverse events of chloroquine use in specific groups, such as during pregnancy and in people with comorbid con- ditions. After the primary and supplemental evidence in humans is presented, sup- porting literature from experimental animal and in vitro studies is then summarized. The chapter ends with a synthesis of all evidence presented by body system and the inferences and conclusions that can be made from the available evidence. FOOD AND DRUG ADMINISTRATION PACKAGE INSERT FOR CHLOROQUINE This section describes selected information in the FDA label or package insert for chloroquine. It begins with information from the most recent label and package insert, detailing contraindications, warnings, and precautions as well as drug interactions known or presumed to occur with concurrent use. It then offers a chronologic overview of changes made to the label. The earliest chloroquine label available on the Drugs@FDA Search site was dated 2003. The overview of label changes is based on information from the 1990 edition of the Physicians Desk Reference and package inserts and letters posted on the Drugs@FDA search site dating from 2003 up to the most recent label, updated in 2018. The adverse events listed in chloroquine’s FDA package insert do not distinguish between adverse events experienced by those using chloroquine for malaria prophylaxis and those using it for malaria treatment, and the list of adverse events appears to be based on non-quantified postmarketing experience (FDA, 2018). Contraindications, Warnings, and Precautions Chloroquine used for malaria prophylaxis is contraindicated in the presence of retinal or visual field changes of any cause (FDA, 2018). It is also contraindicated in persons with known hypersensitivity to 4-aminoquinoline compounds. Users are warned that acute extrapyramidal disorders may occur with chlo- roquine; adverse reactions usually resolve after drug cessation or symptomatic treatment, or both (FDA, 2018). The label warns that cardiomyopathy resulting in cardiac failure, sometimes fatal, has been reported with the long-term, high-dose use of chloroquine (FDA, 2018). Users should be monitored for signs and symptoms of cardiomyopathy and

326 LONG-TERM HEALTH EFFECTS OF ANTIMALARIAL DRUGS should stop the drug if cardiomyopathy develops. If conduction disorders (bundle branch block/atrio-ventricular heart block) are diagnosed, users should stop the drug and be assessed for toxicity. The label states that QT interval prolongation, tor- sades de pointes, and ventricular arrhythmias, sometimes fatal, have been reported, and that high doses increase risk. Chloroquine should be used cautiously in people with cardiac disease, a history of ventricular arrhythmias, uncorrected hypoka- lemia or hypomagnesemia, or bradycardia (˂50 bpm) as well as in those taking QT-interval-prolonging agents owing to the potential for QT-interval prolongation. Irreversible retinal damage has occurred with chloroquine use, and the label states that significant risk factors include daily doses of chloroquine phosphate in amounts >2.3 mg/kg of body weight, administration longer than 5 years, sub- normal glomerular filtration, the use of certain concomitant drug products (e.g., tamoxifen citrate), and concurrent macular disease (FDA, 2018). Chloroquine users should receive a baseline ophthalmologic examination during year 1. Those with significant risk factors should be monitored for retinal damage, including an annual examination; those with no significant risk factors can defer the annual exam to year 5. In individuals of Asian descent, visual field testing should be per- formed in the central 24 degrees. If ocular toxicity is suspected in a chloroquine user, the drug should be stopped and the person observed closely since retinal changes and visual disturbances can progress after drug cessation. The label warns that chloroquine can cause severe hypoglycemia, including a loss of consciousness that could be life threatening in people treated with or without antidiabetic medications (FDA, 2018). Chloroquine users who show clini- cal symptoms of hypoglycemia should be monitored. The label states that those receiving the drug over the long term should be assessed periodically for evidence of muscular weakness and that if weakness occurs, the drug should be stopped. Individuals with psoriasis are warned that chloroquine can trigger a severe attack, and users with porphyria are warned that the drug can exacerbate the con- dition (FDA, 2018). A drug risk–benefit assessment should precede chloroquine use in people with these disorders. People who use the drug over the long term are advised to receive complete blood cell counts periodically. Blood monitoring may be required because chloroquine can cause hemolysis in those with glucose- 6-phosphate dehydrogenase (G6PD) deficiency, particularly when the drug is taken concomitantly with drugs that cause hemolysis. Individuals with preexisting auditory damage should take chloroquine with caution, and if hearing defects occur during use, chloroquine should be stopped and the person observed (FDA, 2018). The drug should be used with caution in those with hepatic disease or alcoholism as well as in those taking hepatotoxic drugs, as chloroquine is known to accumulate in the liver. The label warns that experimental data showed a potential risk of chloroquine inducing gene mutations and states that there is insufficient evidence regarding the drug’s carcinogenicity. In addition, there are insufficient human data to rule out an increased risk of cancer with long-term use (FDA, 2018).

CHLOROQUINE 327 Animal studies showed embryo–fetal developmental toxicity at supra­ therapeutic doses of chloroquine and a potential risk of genotoxicity (FDA, 2018). Human studies, including prospective studies with chloroquine exposure during pregnancy, have found no increase in the rate of birth defects or spontaneous abortions, but an individualized risk–benefit assessment should precede the use of chloroquine by pregnant women. Users are warned that serious adverse reactions in nursing infants can occur when mothers use chloroquine. The label also advises careful dose selection and possible monitoring in those aged ≥65 years; because the drug is substantially excreted by the kidney, the risk of toxic reactions may be greater in patients with impaired renal function, and the elderly are more likely to have decreased renal function. Drug Interactions Drugs that interact with chloroquine include mefloquine (concomitant use increases the risk of convulsions), antacids and kaolin, cimetidine, insulin and other antidiabetic drugs, arrhythmogenic drugs (e.g., amiodarone, moxifloxacin), ampicillin, cyclosporine, praziquantel, and tamoxifen as well as primary immuni- zation with intradermal human diploid-cell rabies vaccine (FDA, 2018). Changes to the Chloroquine Package Insert Over Time Although the Drugs@FDA Search site lists documentation for chloroquine phosphate dating back to the drug’s initial approval in 1949, downloadable docu- mentation for package inserts or labeling is unavailable on the site for the years prior to 2003. The most recent label available on the Drugs@FDA Search site is a 2018 label (Sanofi-Aventis US). Generic formulations of chloroquine phosphate have been manufactured, but only one label (dated 2009) is downloadable from the site. The 2009 label for Aralen® was unavailable for download, so the label from the generic formulation (Hikma Pharms) is used for that year. Aralen® (chlo- roquine phosphate) has been discontinued. An effort has been made to limit the discussion below to label changes that refer to adverse events that occur in adults who use chloroquine as malaria prophylaxis (not for acute attacks of malaria or treatment for other conditions). In 2003 a boxed warning, sometimes informally referred to as a “black box” (FDA, 2003a), was removed from the label. This is FDA’s most serious type of warning, and it appears on a prescription drug’s label to call attention to serious or life-threatening risks (FDA, 2012). The boxed warning had stated, “Physicians should completely familiarize themselves with the complete contents of this leaflet before prescribing Aralen®” (FDA, 2003a). Based on committee review of the ­Aralen® label in the 1990 Physicians Desk Reference, it appears that updates between 1990 and 2003 included cautioning persons with epilepsy that chloro- quine use could cause seizures and warning that the risk of toxic reactions was

328 LONG-TERM HEALTH EFFECTS OF ANTIMALARIAL DRUGS higher in persons with impaired renal function (FDA, 2003b; Physicians Desk Reference, 1990). Delirium, personality changes, and depression were added as adverse reactions. Other additions were cardiomyopathy, myopathy, photosensitiv- ity, and hair loss and bleaching. No source for the adverse reactions (e.g., clinical studies) was provided (FDA, 2003b). Antacids and kaolin, cimetidine, ampicillin, and cyclosporin were added as drug interactions. Language stating that persons who take chloroquine long term be questioned and tested periodically for evidence of muscle weakness was removed from the Warnings section. In the 2009 updates, users were warned that coadministration of chloroquine with mefloquine could increase the risk of convulsions (FDA, 2009). The label also stated that chloroquine could decrease the strength of rabies vaccine. The label added polyneuritis, anxiety, agitation, insomnia, confusion, and hallucinations as adverse reactions. Other additions were rare reports of erythema multiforme, Stevens­ Johnson syndrome, toxic epidermal necrolysis, exfoliative dermatitis and - similar desquamation­ype events; urticaria; anaphylactic/anaphylactoid reaction t including angioedema; and pancytopenia. It was noted that hepatitis can increase the gastrointestinal symptoms experienced with chloroquine use. In the 2013 additions, users were warned that acute extrapyramidal disorders could occur with chloroquine but would usually resolve after stopping the drug or treating the symptoms (FDA, 2013). Users were also warned that retinopathy/ maculopathy and macular degeneration had been reported and that irreversible retina damage in patients taking the drug for long periods or at high doses had been reported. The adverse reactions maculopathy and macular degeneration were noted to be potentially irreversible. In 2017 chloroquine became contraindicated for malaria prophylaxis in patients with retinal or visual field changes (FDA, 2017). Users were warned that cardiac myopathy, sometimes fatal, had been reported in those taking high doses for long periods. Similarly, QT interval prolongation, torsades de pointes, and ventricular arrhythmias, including fatal cases, had been reported and that the risk increased with high doses. The label advised persons with current cardiac prob- lems or a history of cardiac problems to use the drug with caution. Users were also warned of the risk of severe hypoglycemia, which is potentially life threatening, “in patients treated with or without antidiabetic medications.” ­ etinopathy warn- R ings were strengthened. Precautions regarding the use of insulin, other antidiabetic drugs, arrythmogenic drugs, praziquantel, and tamoxifen were added. ­ ensorimotor S disorders were added as an adverse reaction, as was suicidal behavior. Hemolytic anemia in G6PD-deficient patients was noted to be an adverse reaction. In 2018 a warning was added that preclinical data with chloroquine showed a potential risk of gene mutations, and it was noted that there were insufficient data in animals and humans to rule out an increase in cancer risk with the long-term use of chloroquine (FDA, 2018). Users were warned that embryo–fetal develop- mental toxicity had been observed with supratherapeutic doses; in addition, data showed a potential risk of genotoxicity (doses not provided). The label noted that

CHLOROQUINE 329 prophylactic doses did not show an increased rate of birth defects or spontaneous abortions in human studies. Information was added about research on chloroquine and mutagenesis stating that there is some evidence of genotoxic potential but that discrepancies exist in the literature. The label noted that chloroquine (5 mg per day for 30 days) in male rats led to a decrease in testosterone levels and in the weight of the testes, epididymis, seminal vesicles, and prostate; in addition, untreated female rats produced fewer fetuses after mating with males that received injections (10 mg/kg chloroquine for 14 days). The label states that “based on non-Good Laboratory Practice literature reports,” chloroquine at supratherapeutic doses in rats have been found to cause malformations that cause fetal mortality; to cause ocular malformations; and to accumulate in the eyes and ears when administered at the beginning or end of gestation. PHARMACOKINETICS Chloroquine is rapidly absorbed in the gastrointestinal tract and extensively distributed in tissues with a very large volume of distribution that ranges from 200 to 800 L/kg (Ducharme and Farinotti, 1996). As a consequence, distribution rather than elimination processes determines the blood concentration profile of chloro- quine. The oral bioavailability of chloroquine ranges 75–89% (Ducharme and Farinotti, 1996; Krishna and White, 1996; White, 1985). Chloroquine is 50–65% bound to plasma proteins and is cleared equally by the kidney and the liver. Chloroquine undergoes phase I metabolism to form the pharmacologically active desethyl- and bisdesethylchloroquine metabolites. Concentrations of chloroquine and its two major metabolites decline slowly, with elimination half-lives of 20 to 60 days. Chloroquine and desethylchloroquine competitively inhibit CYP2D1/6- mediated metabolic reactions. Existing data suggest that CYP3A and CYP2D6 are the two major CYP450 isoforms affected by, or involved in, chloroquine metabo- lism, which may have implications for potential drug interactions (Ducharme and Farinotti, 1996). Weekly 300 mg oral doses of chloroquine used for prophylaxis result in plasma concentrations up to 0.20 µg/mL (0.62 µM) (Brohult et al., 1979). ADVERSE EVENTS The following section contains a summary of the known concurrent adverse events associated with the use of chloroquine for malaria prophylaxis. Epidemio- logic studies in which information was presented regarding adverse events occur- ring at least 28 days post-chloroquine-cessation are then summarized, with the emphasis on reported results of persistent or latent adverse events associated with the use of chloroquine, including the results of studies in which other antimalarial drugs were used as a comparison group.

330 LONG-TERM HEALTH EFFECTS OF ANTIMALARIAL DRUGS Concurrent Adverse Events The dosing regimens for prophylaxis and treatment vary significantly, and, as with other drugs of interest, individuals using chloroquine for malaria treatment are exposed to a larger dose in a shorter period of time than those using it for malaria prophylaxis. As a result, some adverse events are more prevalent among those using chloroquine for treatment than among those using it for prophylaxis. The committee was unable to identify any systematic reviews examining adverse events that occurred in chloroquine users compared with placebo or nonusers of antimalarial prophylactic drugs. One Cochrane systematic review was identified (Tickell-Painter et al., 2017) that compared the adverse events associated with the use of mefloquine for prophylaxis in nonimmune travelers with adverse events from other antimalarials, including chloroquine, and it is summarized below. Cochrane Reviews Tickell-Painter et al. (2017) prespecified adverse events to include these disorders: psychiatric (abnormal dreams, insomnia, anxiety, depression, psy- chosis); nervous system (dizziness, headaches); ear and labyrinth (vertigo); eye (visual impairment); gastrointestinal (nausea, vomiting, abdominal pain, diarrhea, dyspepsia); and skin and subcutaneous tissue (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 compared with other antimalarials, placebo, or no treatment. The dosages of mefloquine varied, as did the dosages of chloroquine, and the methods of col- lecting adverse event data also varied. 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). The committee recalculated the effect estimates presented below to directly compare chloroquine with mefloquine (instead of mefloquine with chloroquine). In the four cohort studies in the review, 13 serious adverse events were reported in 22,583 chloroquine users, and 29 serious adverse events were reported in 56,674 mefloquine users; the differences between them were not statistically significant (RR = 0.88, 95%CI 0.48–1.61; 79,257 participants). Regarding neurologic adverse events, there was no statistically significant difference between groups in the trials or cohort studies in the proportion of participants reporting headache (RR = 1.19, 95%CI 0.75–1.89; 56,998 participants). Chloroquine users reported statistically significantly less dizziness than mefloquine users in the cohort studies (RR = 0.66, 95%CI 0.59–0.75; 56,710 participants), but this was not observed in the trials (RR = 0.72, 95%CI 0.65–1.46; 569 participants). In single cohort studies, chloro- quine users were less likely to report altered spatial perception (RR = 0.32, 95%CI 0.16–0.65; 2,032 participants) and unsteadiness (RR = 0.28, 95%CI 0.17–0.47; 2,137 participants) than mefloquine users. Tingling was reported in two cohort

CHLOROQUINE 331 studies and was statistically significantly less common in chloroquine users than in mefloquine users (RR = 0.45, 95%CI 0.25–0.79; 2,778 participants). Four trials were included, and no serious adverse events were reported among 471 chloroquine users, while two serious adverse events were reported among 529 mefloquine users; the difference between the groups was not statistically signifi- cant (RR = 0.36, 95%CI 0.04–2.77), but the estimate was imprecise. Chloroquine users were statistically significantly less likely than mefloquine users to report the psychologic adverse events of abnormal dreams (RR = 0.83, 95%CI 0.75–0.91), anxiety (RR = 0.16, 95%CI 0.11–0.23), depressed mood (RR = 0.32, 95%CI 0.12– 0.87), and abnormal thoughts or behavior (RR = 0.18, 95%CI 0.09–0.38) across the included cohort studies. Abnormal dreams was the only psychiatric outcome reported by the trials and the risk of it was also statistically significantly decreased with chloroquine use compared with mefloquine use in the trials. Insomnia was reported by five cohort studies (RR = 0.55, 95%CI 0.22–1.37; 56,952 participants) and two trials (RR = 0.84, 95%CI 0.54–1.32; 359 participants), and there were no statistically significant differences observed between chloroquine and mefloquine users. No statistically significant differences were found between chloroquine and mefloquine users for experiencing anger, disturbance in attention, irritability, loss of appetite, malaise, or altered mood. When mefloquine users were compared with chloroquine users, there was no statistically significant difference for nausea, vomiting, or abdominal pain. Over- all, mefloquine users were less likely to report diarrhea, but that finding was based primarily on the results from a single cohort study that contributed more than 90% of the weight in the meta-analysis (RR = 0.84, 95%CI 0.74–0.95; 5 cohort studies, 5,577 participants). Other symptoms were also included when available. No statistically sig- nificant differences were found between chloroquine and mefloquine users for experiencing pruritus or abdominal distension. Several outcomes were reported in only one or two cohort studies. For example, in single cohort studies chloroquine users were less likely than mefloquine users to report alopecia (RR = 0.59, 95%CI 0.44–0.79) and visual impairment (RR = 1.10, 95%CI 0.01–2.44; 5 cohort ­ tudies, s 58,847 participants). Post-Cessation Adverse Events A total of 17,337 abstracts or titles were identified by the committee for inclu- sion for chloroquine. After an initial evaluation of the types of citations captured, the committee determined that a large portion of the literature contained informa- tion related to alternative uses of chloroquine (e.g., rheumatoid arthritis, cancer, systemic lupus erythematosus). Additional search terms related to prophylaxis and malaria were added, which reduced the number of captured citations to 4,106. After screening, 791 abstracts and titles remained, and the full text for each was retrieved and reviewed to determine whether it met the committee’s inclusion

332 LONG-TERM HEALTH EFFECTS OF ANTIMALARIAL DRUGS criteria, as defined in Chapter 3. The committee reviewed each article and identi- fied three primary epidemiologic studies that met its inclusion criteria, including a mention of adverse events (or that no adverse events were observed) that occurred ≥28 days post-cessation of chloroquine (Lege-Oguntoye et al., 1990; Schneider- man et al., 2018; Tan et al., 2017). A table that gives a high-level comparison (study design, population, exposure groups, and outcomes examined by body system) of each of these three epidemiologic studies is presented in Appendix C. Military and Veterans Schneiderman et al. (2018) conducted a retrospective observational analysis of self-reported health outcomes associated with the use of antimalarial drugs in a cohort of U.S. veterans who had responded to the 2009–2011 National Health Study for a New Generation of U.S. Veterans (referred to as the “NewGen Study”). The NewGen Study is a population-based survey that sampled 30,000 veterans who had been deployed to Iraq or Afghanistan between 2001 and 2008 and 30,000 nondeployed veterans who had served during the same time period, and it included a 20% oversampling of women. The survey was conducted using mail, telephone, and web-based collection, and it yielded a response rate of only 34.3%. For this particular analysis, 19,487 participants were included who had self-reported their history of antimalarial medication use, and the use was grouped for analysis by drug (mefloquine, chloroquine, doxycycline, primaquine, mefloquine in combi- nation with other drugs, other antimalarials, and not specified) or no antimalarial use. Health outcomes were self-reported using standardized instruments: the Medical Outcomes Study 12-item Short Form (SF-12) for general health status, PTSD checklist–Civilian version (PCL-C), and the Patient Health Questionnaire (PHQ). These instruments yielded scores that were dichotomized for analysis on composite physical health, composite mental health (above or below the U.S. mean), posttraumatic stress disorder (PTSD) (above or below the screening cut- off), thoughts of death or self-harm, other anxiety disorders, and major depression. Potential confounders included in multivariate analysis were the branch of service, sex, age, education, race/ethnicity, household income, employment status, marital status, and self-reported exposure to combat. Responses were weighted to account for survey non-response. Most veterans reported no antimalarial drug exposures (61.4%, n = 11,100), and these served as the referent group. When stratified by deployment status, among the deployed (n = 12,456), of those who reported using an antimalarial drug (n = 6,650), 274 (weighted 3.5%) veterans reported using only chloroquine and 425 (weighted 6.0%) reported using mefloquine and another antimalarial, which may have included chloroquine. Among the nondeployed (n = 7,031), 110 (weighted 5.8%) used chloroquine alone and 52 (weighted 2.8%) reported using mefloquine and another antimalarial, which may have included chloroquine. Because it is not clear how many people in the mefloquine-plus group may have also used chloroquine, the results of that

CHLOROQUINE 333 group are not included in the committee’s assessment. The deployed chloroquine users reported increased frequencies of mental health diagnoses compared with nondeployed chloroquine users: PTSD (18.9% versus 7.4%), other anxiety disor- ders (10.4% versus 2.5%), major depression (11.4% versus 4.5%), and thoughts of death or self-harm (12.8% versus 9.2%), but no statistical comparisons were presented. In the adjusted logistic regression models with all the covariates con- sidered (including demographics, deployment, and combat exposure), chloroquine use was not associated with any of the health outcomes when compared with no antimalarial use: composite mental health score (OR = 1.15, 95%CI 0.88–1.50), composite physical health score (OR = 1.15, 95%CI 0.88–1.50), PTSD (OR = 0.89, 95%CI 0.6–1.33), thoughts of death or self-harm (OR = 0.94, 95%CI 0.62–1.42), other anxiety (OR = 0.66, 95%CI 0.40–1.06), and major depression (not adjusted for combat exposure) (OR = 0.96, 95%CI 0.63–1.47). The analysis of the NewGen survey is highly relevant to the question of whether there are adverse events of chloroquine use that persist following drug cessation. The study was large enough to generate moderately precise measures of association, specific drugs were assessed, the outcomes were based on stan- dardized instruments (although not face-to-face diagnostic interviews), important covariates of deployment and combat exposure were considered in addition to demographics and other military characteristics, and the data were appropriately analyzed. The number of chloroquine users in this sample was small. It is note- worthy that adjusting for combat exposure consistently reduced the measures of association, potentially indicating a strong confounding effect of combat exposure. Although the time period of drug use and the timing of health outcomes were not directly addressed, given that the populations were all veterans who had served between 2001 and 2008 and the survey was not administered until 2009–2011, it is reasonable to assume that antimalarial drug use had ceased some time before the survey. Nonetheless, the study could not address explicitly the health experiences during use and in specific time intervals following the cessation of use. There are a number of methodologic concerns that limit the strength of this study’s find- ings. The low response rate of 34% raises concerns of non-response bias, but the responses were weighted to account for non-response. Selective participation by both antimalarial drug use history and health status would be required to introduce bias. The accuracy of self-reported antimalarial drug use in this population is unknown. Although self-reported information has some advantages over studies based on prescriptions in that the individual specifically recalls using the drug, the details about the reported drug and adherence are not validated. Self-reported health experience is subject to the usual disadvantages of recall bias and the bias of reporting subjective experience without an independent expert assessment; however, by using standardized assessment tools, these biases may have been circumvented to some extent.

334 LONG-TERM HEALTH EFFECTS OF ANTIMALARIAL DRUGS U.S. Peace Corps Tan et al. (2017) conducted a retrospective observational Internet-based sur- vey of 8,931 (11% response rate) returned U.S. Peace Corps volunteers (who had served during 1995–2014) 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 antimalarial pro- phylactic prescriptions were mefloquine (n = 2,981; 59.0%), atovaquone/proguanil (A/P) (n = 183, 3.6%), chloroquine (n = 674, 13.3%), doxycycline (831, 16.4%), and “other” prophylactic medications (n = 386, 7.6%). In addition to questions on malaria prophylaxis (type, regimen, duration, and adherence), the survey included questions about the country of service, the type of assignment, and whether malaria prophylaxis was required at the assigned site. Respondents were also asked to report medical diagnoses made by a health care provider before, during, and after serving in the Peace Corps; to answer questions about medications used before, during, or after Peace Corps service; to provide a family history of disease and psychiatric illness; to describe their psychiatric history prior to exposure; and to give details about alcohol consumption. In total, more than 40 disease outcomes were examined for associations with each antimalarial, including derived out- comes of major depressive disorder, bipolar disorder, anxiety disorder, insomnia, psychoses, and cancers. Outcomes were grouped by system (neuropsychologic, cardiac, ­ phthalmologic, dermatologic, reproductive, and gastrointestinal) or class o (infectious, hematologic/oncologic) and within each group several diagnoses were listed. “Any psychiatric outcome” included all reported psychiatric diagnoses both derived and those reported as individual diagnoses, including schizophrenia, obsessive-compulsive disorder, and “other.” Neuropsychologic disorders were presented as a category and separately included dementia, migraines, seizures, tinnitus, vestibular disorder, “other” neurologic disorder, and “any” neurologic disorder. Gastrointestinal diseases were the only diagnosis statistically signifi- cantly more prevalent among Peace Corps volunteers who had used any chloro- quine than among those who had not (9.1% versus 6.7%, respectively; prevalence ratio = 1.40, 95%CI 1.10–1.79). There was no difference in the prevalence of gastrointestinal diseases between those with prolonged or prolonged exclusively chloroquine use and those with no chloroquine use. The study reported that the prevalences of other disease diagnoses extrapolated from adverse events derived from reported and feared adverse events were similar between the groups, includ- ing those diagnoses that previous studies had indicated might be associated with chloroquine use, such as ocular toxicity. The study had many limitations, primarily stemming from its design as an Internet-based survey of people with an email address on file. The response rate was low (11%), the authors relied on self-report for both exposure and outcome informa- tion and the timing of each, and for some participants the time between drug expo- sure and the survey was many years. Most comparisons were between those who

CHLOROQUINE 335 had been exposed to a specific drug (i.e., mefloquine, chloroquine, doxycycline, A/P, other) and those who had not. Thus, the comparison group for each anti­ alarial m was a mixture of those who did not report taking any anti­ alarials and those who m reported taking antimalarial drugs other than the one being examined. Overall, there were few details of the limited analyses presented, which made 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 ­ odels. The reliance m on self-report, often years (range 2–20 years) after the exposure, introduced several potential biases (selection bias, recall bias, and confounding bias), with inadequate information to determine the likely impact or direction of the potential biases act- ing in this study. While the use of self-reported diagnoses that were specified to be those made by a medical professional to ascertain health outcomes was arguably a better method than using a checklist of symptoms, the outcomes were not validated against any objective information. While the results presented in this study do not support the presence of persistent adverse events, or neuropsychiatric events, spe- cifically post-cessation of chloroquine, the design limitations of this study are such that any evidence provided by this study is weak. Research Volunteers Lege-Oguntoye et al. (1990) conducted a nonblinded randomized controlled trial to study the effect of chloroquine on the humoral and cell-mediated immunity of semi-immune adult volunteers in Zaria, Nigeria. Thirty subjects were block ran- domized to chloroquine (n = 20) or control (n = 10) and given weekly dosing for a period of 6 months; three individuals in the chloroquine group were excluded from analysis due to poor adherence. Drugs were orally administered under supervi- sion from March 1986 through December 1986. Blood measures were obtained at baseline, 3 months, and 6 months after starting the prophylaxis and 2 months after drug cessation. None of the 27 enrolled individuals had detectable drug plasma concentrations at enrollment. After 3 months of chloroquine dosing, indirect immunofluorescence assay titers to P. falciparum declined and further decreased throughout the study; the effect lasted up to 2 months post-chloroquine-cessation. Furthermore, after 3 months of chloroquine dosing, serum concentrations of IgG and IgM were significantly reduced. Two months after drug cessation, the serum concentrations of IgG and factor B were significantly reduced. The investigators hypothesized that the secretory processes of the macrophage–monocyte system are generally inhibited by the use of chloroquine; the implication of significant short-term or long-term use of chloroquine prophylaxis may be the predisposition of the subjects to bacterial infections by organisms with capsular polysaccharide that depend on the alternative pathway for effective clearance. No changes were found for serum C3C or C4 for either group. Lymphocyte counts were unchanged throughout the study period. The details of the statistical differences between study groups in outcomes were not presented. In summary, the study found some

336 LONG-TERM HEALTH EFFECTS OF ANTIMALARIAL DRUGS changes in immune response that persisted for 2 months after drug cessation. How- ever, the study had a very small sample size and presented data related to only a limited number of outcomes. The measures of immunity are intermediate, and the relationship to clinical outcomes is unknown. OTHER IDENTIFIED STUDIES OF CHLOROQUINE PROPHYLAXIS IN HUMAN POPULATIONS When reviewing full-text articles, the committee identified several epide- miologic articles on chloroquine use for malaria prophylaxis that could not be included because they either did not provide information on adverse events that occurred ≥28 days post-cessation of chloroquine or presented data that did not distinguish among adverse events that occurred during concurrent use of chloro- quine or ≥28 days post-cessation of chloroquine. These studies include Baird et al. (1995), Barrett et al. (1996), Boudreau et al. (1991, 1993), Bustos et al. (1994), C ­ unningham et al. (2014), Fryauff et al. (1996), Handschin et al. (1997), Harries et al. (1988), Hill (2000), Hilton et al. (1989), Huzly et al. (1996), Korhonen et al. (2007), ­ averone et al. (2006), Lobel et al. (1991, 1993), Petersen et al. (2000), L R ­ oestenberg et al. (2009, 2011), Sharafeldin et al. (2010), Sossouhounto et al. (1995), Steffen et al. (1990, 1993), Stemberger et al. (1984), Sturchler et al. (1987), Waner et al. (1999), and Winkler (1970). Additionally, three articles included for consideration within other drug chapters only reported exposure as “chloroquine and/or proguanil” in the study results. These articles did not distinguish between adverse events associated with chloroquine alone, chloroquine and proguanil, or proguanil alone; therefore, they were not considered by the committee for this chapter. The studies were Meier et al. (2004) and Schneider et al. (2013, 2014). Upon full-text review and quality assessment, additional studies were excluded from further consideration. Bijker et al. (2014) conducted a double-blind randomized controlled trial of experimental infection 16 weeks following the administration of prophylactic doses of mefloquine (n = 10) or chloroquine (n = 5) in healthy volun- teers in the Netherlands. Adverse events and their severity were recorded over the duration of the study; all adverse events were reported to have resolved by the end of the study, but because the exact timing of the resolution was not provided, this study was not included in the primary epidemiologic studies. Bunnag et al. (1992) conducted a randomized double-blind study comparing the efficacy and tolerability of Fansimef®, mefloquine, Fansidar®, and chloroquine to placebo for malaria pro- phylaxis in 602 healthy adult males in Thailand who were followed for 4 weeks after the final dose. The timing of the adverse events was not specified, although blood measures were reported to remain stable throughout the study period, but because the details were not presented, the study did not meet the inclusion criteria. Salako et al. (1992) conducted a randomized double-blind trial to assess the efficacy of ­ ansimef®, mefloquine, Fansidar®, and chloroquine compared with placebo. Follow- F

CHLOROQUINE 337 up was continued for 4 weeks after the cessation of prophylaxis, but neither the details of which data were collected during those 4 weeks nor the timing of adverse events were provided, and thus this study did not meet inclusion as a primary epide- miologic study. Finally, Shanks et al. (1993) compared the efficacy of post-exposure malaria prophylaxis of two dosages of halofantrine and chloroquine among copper mine workers returning from Papua New Guinea; 400 were successfully followed for 28 days post-drug-administration. Adverse events were not collected in a sys- tematic way, and their timing was not specified. Case Reports and Case Series Chloroquine exposure has been associated with “chloroquine retinopathy,” an eye condition that can lead to persistent visual dysfunction and even blindness. Numerous case studies of retinopathy have appeared in the literature, typically in the context of chloroquine taken in larger doses than prescribed for malaria pro- phylaxis; however, only adverse events in people who used chloroquine to prevent malaria are considered here. The committee reviewed three case studies and five published reports of other adverse events associated with chloroquine use (n = 80). Neurologic disorders were found in three patients: two cases of neuro­ yopathy, m both of which occurred in people who were taking doses of chloroquine that were much higher than the recommended dose for malaria prophylaxis (­ arstorp et al., K 1973; Tegner et al., 1988), and one case where an electro­ ncephalogram was sug- e gestive of a diagnosis of nonconvulsive complex partial status epilepticus, which resolved by 2 months post-chloroquine-cessation ­ Mulhauser et al., 1995). In the ( case reported by Karstorp et al. (1973), muscle strength and reflexes returned to normal by 3 months post-cessation, but the case reported in Tegner et al. was found to have morphologic changes in Schwann cells upon autopsy. Other cases of adverse events were reported. Spira (1997) reported a patient with desquamation and symmetrical hypopigmentaion of the hands, which improved at 4 weeks post-chloroquine-cessation and resolved completely by 3-month follow-up. Sensory disorders were associated with chloroquine expo- sure in a few patients as reported in several studies. Kokong et al. (2014) found ­ totoxicity resulting in hearing loss in individuals taking chloroquine. ­ ertagnolio o B et al. (2001) reported persistent retinopathy in one patient, and Ferrucci et al. (1998) reported an exacerbation of retinitis pigmentosa. Lange et al. (1994) studied 588 missionaries who had previously used chloroquine for malaria prophylaxis and conducted physical examinations on a subset of 53 individuals. A detailed medical history was conducted that included medication exposures and completion of a visual examination. One participant was diagnosed with chloroquine ­ etinopathy, r including blurred vision, blind spots, photophobia, eye pain, and clinical findings of ring scotoma, retinal pigment changes endothelial dystrophy, and macular degeneration; however, this patient used chloroquine for a connective tissue dis- order, and not solely for malaria prophylaxis. No other diagnoses of ­ etinopathy r

338 LONG-TERM HEALTH EFFECTS OF ANTIMALARIAL DRUGS were discovered. And Munera et al. (1997) wrote of a case of elevated thyroid stimulating hormone that was presumed to stem from chloroquine exposure. Selected Subpopulations In the course of its review of the literature on chloroquine, the committee iden- tified and reviewed available studies that reported results stratified by demographic, medical, or behavioral factors to assess whether the risk for adverse events when using chloroquine for prophylaxis is associated with being part of or affiliated with a specific group. This was not done exhaustively, and the evidence included in this section is generally limited to adverse events observed with concurrent use of chloroquine. Many of these studies did not meet the inclusion criteria of following their population for at least 28 days post-chloroquine-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 individuals with comorbid diseases. Pregnancy Chloroquine is considered to be safe for malaria prophylaxis in all trimes- ters of pregnancy (Moore and Davis, 2018). Chloroquine has not been found to have harmful effects on the fetus when it is used in the recommended doses for malaria prophylaxis (McGready et al., 2002; Villegas et al., 2007). For example, in a cohort of U.S. government employees taking chloroquine (300 mg weekly) as prophylaxis throughout pregnancy in 1969–1978, the prevalence of newborns with congenital abnormality (1.2%, 2/169) was not different from that among those who were not exposed to chloroquine (0.9%, 4/454) (Wolfe and Cordero, 1985). The Centers for Disease Control and Prevention states that chloroquine can be used for malaria prophylaxis during all trimesters of pregnancy, but only in destinations where chloroquine resistance is not present (CDC, 2019). A pharmacokinetic study of chloroquine during pregnancy found increased drug metabolism and clear- ance rates and decreased blood levels as compared with a nonpregnant group, thus allowing the authors to recommend a 33% increase in chloroquine doses in pregnant women based on a detailed computational analysis (Salman et al., 2017). Comorbid Diseases Amet et al. (2013) suggests that reductions be made to chloroquine prophylac- tic dosing regimens in individuals with decreased creatinine clearance (a measure of renal compromise). Chloroquine can produce retinal effects, albeit at a very low rate (Labriola et al., 2012), a fact that reinforces the need for long-term monitoring of retinal and visual changes. In critically ill individuals, chloroquine may increase the risk of developing drug-induced acute liver failure (Lat et al., 2010). Caution

CHLOROQUINE 339 should be used when prescribing chloroquine to elderly adults, particularly those suffering from blood dyscrasias, psoriasis, porphyria, or liver disease or who engage in heavy alcohol consumption (Yax et al., 2007). BIOLOGIC PLAUSIBILITY Some in vitro and in vivo studies suggest that chloroquine may benefit neu- rologic outcomes following stroke or neurotoxic challenge, perhaps via PLA2 inhibition (Farooqui et al., 2006); however, other studies in neuronal and astrocyte cell lines suggest that high doses of chloroquine result in neurotoxicity, thought to be mediated by mitochondrial oxidative stress (Woerhling et al., 2010). In addi- tion, chloroquine promotes the generation of reactive oxygen species in human astrocyte cultures, increasing chemokine production, which is suggestive of local inflammation (Park et al., 2004). Binding studies indicate that chloroquine can bind (and act as a competitive inhibitor of) the mu (µ), delta (δ), and kappa (κ) opioid receptors with low micromolar affinity. Drug levels of chloroquine can approach 1 µM during prophylactic dosing, so it is possible that this drug perturbs opioid signaling (Liu et al., 1991). However, chloroquine does not bind GABA, serotonin, or dopamine receptors to any significant extent (Janowsky et al., 2014; Liu et al., 1991). While these data were based on generally very high doses of chloroquine, the experimental evidence suggests a means for chloroquine to affect neuronal health and viability (beneficially for some outcomes, deleteriously for others), although the specific actions on neurologic and psychiatric endpoints have not been definitively examined in vivo. There is evidence that chloroquine can prolong QT interval at curative doses in patients, but it does not provoke overt cardiac symptoms and remits with discontinuation of therapy (Bustos et al., 1994). Chloroquine also affects action potential velocity, duration, and refractory period in sheep Purkinje fibers of the heart, a phenomenon that may be related to anti-arrhythmic actions of chloroquine in cardiac patients (thought to be linked to PLA2 inhibition) (Harris et al., 1988; Tobón et al., 2019). There is evidence for deleterious actions of chloroquine on the retinal pig- ment epithelium, which can cause visual disturbances and macular degeneration in patients receiving anti-inflammatory dosing for the treatment of autoimmune diseases (e.g., systemic lupus erythematosus) for which the recommended doses are much higher than the dose used for malaria prophylaxis. It is postulated that retinal pigment changes may also be seen following short-term prophylactic dos- ing regimens (Rimpela et al., 2018); however, the committee did not find any evidence to support this hypothesis during the review of the available research. These changes may be the result of an elevation in the lysosomal pH in the retinal pigment epithelium (Audo and Warchol, 2012) and possibly by the binding of chloroquine to melanin (Rimpela et al., 2018).

340 LONG-TERM HEALTH EFFECTS OF ANTIMALARIAL DRUGS In addition to being an efficacious antimalarial drug, chloroquine has also gained usage as an anti-inflammatory agent and is used at high doses in the treat- ment of autoimmune diseases, including systemic lupus erythematosus, rheumatoid arthritis, and Sjögren’s syndrome (Dai et al., 2018). Its anti-inflammatory actions are thought to be mediated largely via its actions as a lyso­ omotrophic agent, s increasing intra-lysosomal pH by acting as a diprotic weak base (­ ccapezzato A et al., 2005; Fox and Kang, 1993). As reviewed by Galluzzi et al. (2017) and He et al. (2018), chloroquine inhibits autophagy by deacidifying the lysosome. Autophagy is a lysosome-dependent survival pathway of intracellular degrada- tion that maintains cellular homeostasis. Chloroquine can also decrease cytokine production (e.g., TNFα, IL-6) by altering iron metabolism (Picot et al., 1993) or via the inhibition of toll-like receptor 3 signaling cascades in immune cells, indica- tive of anti-inflammatory actions (Aizawa et al., 2019; Cui et al., 2013; Imaizumi et al., 2017). Chloroquine also inhibits PLA2, a membrane protein important in cellular signaling cascades (Bondeson and Sundler, 1998). Some data suggests that chloroquine prophylaxis can decrease the levels of immunoglobins and T- and B-cells (Lege-Oguntoye et al., 1990); it is possible that immunosuppression actions could impair resistance to infection. Osorio et al. (1992) examined the effects of chloroquine at prophylactic doses on the phagocytic function of human monocytes and suggested that immune consequences may be associated with the use of chloroquine for malaria prophylaxis, but these results are limited and only weakly supportive of the findings of Lege-Oguntoye et al. (1990). SYNTHESIS AND CONCLUSIONS Even though chloroquine has been approved by FDA for malaria prophylaxis for more than 70 years, only three epidemiologic studies were identified that included some mention of adverse events or data collection that occurred ≥28 days post-cessation of chloroquine and that provided directly relevant information for assessing persistent or latent adverse events (Lege-Oguntoye et al., 1990; Schneiderman et al., 2018; Tan et al., 2017). The studies are heterogeneous in the populations that were used (endemic populations, U.S. military veterans, and returned U.S. Peace Corps volunteers, respectively); in the modes of data collec- tion on drug exposure, health outcomes, and covariates (administrative records, researcher collected, self-report, respectively); and particularly in the nature of the health outcomes that were considered. Within a particular outcome category, such as psychiatric conditions, the information elicited ranged from more minor symptoms (such as anxiety) to severe clinical disorders (e.g., psychosis, depres- sion, PTSD), posing a challenge to the committee’s ability to make an integrated assessment. Furthermore, the relevant studies were notably inconsistent in their reporting of results, covering different time periods relative to the cessation of the drug exposure. Given the inherently imperfect information generated by any

CHLOROQUINE 341 one study, it would be desirable to have similar studies to assess the consistency of the findings, but the diversity of the methods in these three studies made it very difficult to combine information across studies with confidence. Each of the post-cessation epidemiologic studies possessed strengths and weaknesses related to the specific methodology used by the investigators during the study process. The studies are notably different in methodologic quality, so their findings are not weighted equally in drawing conclusions. Based on the methodologic consider- ations described in Chapter 3, a brief summary of the committee’s evaluation of each post-cessation epidemiologic study is described here, and findings specific to each body system are presented below, as appropriate. Each conclusion consists of two parts: the first sentence assigns the level of association, and the second sentence offers additional detail regarding whether further research in a particular area is merited based on a consideration of all the available evidence. Epidemiologic Studies Presenting Contributory Evidence Schneiderman et al. (2018) conducted an analysis of self-reported health outcomes associated with use of antimalarials in a population-based cohort study of deployed and nondeployed U.S. veterans, using information collected as a part of the NewGen Study. Exposures and outcomes were systematically obtained, and psychiatric outcomes were measured by standardized assessment instruments. Antimalarial medication use was grouped into mefloquine, chloroquine, doxycy- cline, primaquine, mefloquine in combination with other drugs, other antimalari- als, and not specified or no antimalarial drug exposures. Health outcomes were self-reported using standardized instruments: the SF-12 for general health status, PCL-C for PTSD, and the PHQ. The overall sample was large, and the researchers used a reasonably thorough set of covariates in models estimating drug–outcome associations, including deployment and combat exposure. Although the time period of drug use and the timing of health outcomes were not directly addressed, given that the population comprised veterans who had served between 2001 and 2008 and that the survey was not administered until 2009–2011, it is reasonable to assume that antimalarial drug use had ceased some time before the survey. The methodology and response rate (34% total; weighted 3.5% of deployed and weighted 5.8% of nondeployed individuals used chloroquine) for this study may have led to the introduction of non-response, recall, or selection biases; however, the committee believes that the investigators used appropriate data analysis tech- niques to mitigate the effects of any biases that were present. The primary aim of Tan et al. (2017) was to assess the prevalence of several conditions experienced by returned U.S. Peace Corps volunteers and their associa- tion with the use of prophylactic antimalarial medications. Although the number of participants was large (8,931 participants) and a number of important covariates, such as psychiatric history and alcohol use, were collected, the study had several methodologic issues. These limitations included the study design (self-report,

342 LONG-TERM HEALTH EFFECTS OF ANTIMALARIAL DRUGS Internet-based survey), exposure characterization (reliance on self-reported expo- sure introduces several potential biases, such as recall bias, sampling bias, and confounding), the outcome assessment (based on self-report of health provider– diagnosed conditions up to 20 years post-service), the use of mixed comparison groups, the lack of detail regarding the analysis methods, and a poor response rate (11%, which likely introduced selection bias). Additionally, only 674 (13.3%) of the respondents reported using chloroquine for primary malaria prophylaxis. The evidence generated by this study was thus considered to only weakly contribute to the inferences of persistent adverse events or disorders associated with chloroquine use for malaria prophylaxis. The primary objective of the study conducted by Lege-Oguntoye et al. (1990) was to examine the effects of short-term chloroquine use for malaria prophylaxis on the humoral and cell-mediated immunity of healthy semi-immune adults. Inves- tigators analyzed changes in biochemical parameters within individuals taking chloroquine for 6 months and then followed the individuals for 2 months post- chloroquine-cessation. In the committee’s view, the use of standardized laboratory testing and procedures in this study reduces the likelihood of the introduction of bias and likely indicates that the data presented are of high quality. However, the committee believed that the limitations of the endpoints tested did not allow for the conclusion that there is a significant impact of chloroquine on immune function. This study also had a very small sample size (n = 27), and investigators examined and reported only intermediate measures of immunity with unknown clinical implications, limiting the information that could be gleaned from the study findings; therefore, this study was given less weight in the committee’s forming of conclusions regarding the persistent or latent adverse events of chloroquine use as malaria prophylaxis. In addition to the epidemiologic studies, the committee also considered supplemental evidence, including recognized concurrent adverse events, case reports of persistent adverse events, studies of adverse events in pregnant women and people with comorbid conditions, and information from experimental animal models or cell cultures. Consistent with the chapter syntheses of other antimalarial drugs, the synthesis is organized by body system category: neurologic disorders, psychiatric disorders, gastrointestinal disorders, eye disorders, cardiovascular dis- orders, and other disorders, including immunologic and dermatologic outcomes. Neurologic Disorders Although some studies grouped adverse events under a more general category of “neuropsychiatric” effects for discussion, the committee separated neurologic and psychiatric symptoms and conditions to the extent possible. An examination of the associations between chloroquine use and neurologic disorders does not indicate an increased risk for current chloroquine users, with the exception of the indication in the FDA label and package insert that muscle weakness may be

CHLOROQUINE 343 associated with chloroquine use and that individuals with a history of epilepsy should be warned about the risk of chloroquine provoking seizures. According to a systematic review examining concurrent adverse events experienced by short-term travelers, risk of altered spatial perception, unsteadiness, and tingling were statisti- cally significantly reduced in individuals using chloroquine compared with meflo- quine (Tickell-Painter et al., 2017). The committee identified three case reports: one case of neuromyopathy that had fully resolved by 3 months post-chloroquine- withdrawal (Karstorp et al., 1973); one case study reporting symptoms of motor dysphagia and language problems, with an electroencephalogram suggestive of a diagnosis of nonconvulsive complex partial status epilepticus (Mulhauser et al., 1995); and one case that reported autopsy findings of morphologic changes to Schwann cells (Tegner et al., 1988). Preclinical studies do not indicate that c ­ hloroquine has marked neurotoxic effects, although alterations in astrocyte func- tion have been noted, suggesting possible neuromodulary actions. Of the three post-cessation epidemiologic studies that examined chloroquine use, Tan et al. (2017) was the only one that examined neurologic health outcomes, including migraines, seizures, tinnitus, vestibular disorder, “other neuropsycho- logic” disorders, and “any neuropsychologic” disorder. The investigators reported no difference in the rates of “neuropsychological” outcomes between users of chloroquine and nonusers of chloroquine; however, the limitations of the study design, as previously described, provide weak inferences. Based on the available evidence, the committee concludes that there is insuf- ficient or inadequate evidence of an association between the use of chloroquine 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 concur- rent use, or findings from the existing epidemiologic studies. Psychiatric Disorders The FDA label or package insert for chloroquine lists psychosis, delirium, anxiety, agitation, insomnia, confusion, hallucinations, personality changes, and depression as potential psychiatric adverse events that may occur in individuals taking chloroquine. However, in a systematic review examining concurrent adverse events experienced by short-term travelers, chloroquine users were statistically significantly less likely than mefloquine users to report such psychologic adverse events as abnormal dreams, anxiety, depressed mood, and abnormal thoughts or behavior (Tickell-Painter et al., 2017). No statistically significant differences were found between chloroquine and mefloquine users for experiencing anger, distur- bance in attention, irritability, malaise, or altered mood. No published case studies were identified that presented information on psychiatric adverse events associated with chloroquine use when used at the dosing regimen for malaria prophylaxis that developed or persisted for ≥28 days post-cessation of chloroquine. Experimental

344 LONG-TERM HEALTH EFFECTS OF ANTIMALARIAL DRUGS animal studies and other biologic plausibility studies identified by the committee provided no evidence of persistent or latent adverse psychiatric events associated with chloroquine use for malaria prophylaxis. Two of the epidemiologic studies assessed included information on at least one psychiatric outcome: one in military populations (Schneiderman et al., 2018) and one in returned U.S. Peace Corps volunteers (Tan et al., 2017). The two s ­ tudies used different methods for measuring outcomes—unverified self-reported clinical diagnoses (Tan et al., 2017) and standardized self-report instruments (­ chneiderman et al., 2018)—with little overlap in the specific outcomes examined S across the two studies. For example, PTSD was included in Schneiderman et al. (2018) but not in Tan et al. (2017). Similarly, insomnia was included in Tan et al. (2017), but not in Schneiderman et al. (2018). Notably, both studies collected data on depression and anxiety, but in different ways. Schneiderman et al. (2018) used a validated, standardized, mental health questionnaire and recorded a diagno- sis based on the total score, whereas Tan et al. (2017) used unverified self-reported symptoms to derive diagnoses of major depressive disorder, bipolar disorder, anxi- ety disorder, schizophrenia, and a category of “other” mental health disorders from these symptoms. The diagnosis classification methods used by Tan et al. (2017) may have introduced nondifferential misclassification of the outcomes; however, the committee believed this was unlikely to affect study findings. In terms of results, Tan et al. (2017) reported no associations between chloro­ quine exposure and the psychiatric outcomes examined (depressive disorder, bipolar disorder, anxiety disorder, psychosis, and insomnia). In Schneiderman et al. (2018), the deployed chloroquine users reported increased frequencies of mental health diagnoses compared with nondeployed chloroquine users: PTSD (18.9% ver- sus 7.4%), other anxiety disorders (10.4% versus 2.5%), major depression (11.4% versus 4.5%), and thoughts of death or self-harm (12.8% versus 9.2%), but no for- mal statistical inferences were made. In the adjusted logistic regression models that adjusted for demographics, deployment, and combat exposure, the use of chloro- quine was not statistically significantly associated with any of the psychiatric health outcomes—composite mental health score, PTSD, thoughts of death or self-harm, other anxiety, and major depression (not adjusted for combat exposure)—when compared with nonusers of antimalarial drugs. Notably, adjustment for combat exposure consistently reduced the measures of association for psychiatric outcomes related to chloroquine use. This study provides modest evidence of no increase in risk of persistent or latent psychiatric adverse events of chloroquine in terms of PTSD, anxiety disorders, major depression, or thoughts of death or self-harm. Based on the available evidence, the committee concludes that there is insuf- ficient or inadequate evidence of an association between the use of chloroquine for malaria prophylaxis and persistent or latent psychiatric 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.

CHLOROQUINE 345 Gastrointestinal Disorders Chloroquine is known to accumulate in the liver, and the package insert warns that caution should be used in individuals with hepatic disease or alcoholism or who are using known hepatotoxic drugs. Likewise, chloroquine-induced hepatitis has been reported in studies examining concurrent adverse events of chloroquine use. This effect may be more likely in critically ill individuals. Experimental ani- mal and human cell culture studies that used chloroquine were also examined for evidence of mechanisms that could plausibly support persistent or latent adverse events, and the committee found no information indicating that chloroquine use is associated with persistent or latent gastrointestinal adverse events. In a systematic review examining concurrent adverse events experienced by short-term travelers, no statistically significant differences were found between chloroquine and meflo- quine users for experiencing nausea, vomiting, or abdominal pain. Chloroquine users were more likely to report diarrhea, but that finding was based primarily on the results from a single cohort study that contributed to more than 90% of the weight in the meta-analysis. The committee identified one post-cessation epidemiologic study that exam- ined persistent gastrointestinal adverse events associated with chloroquine use (Tan et al., 2017). Tan et al. (2017) reported that gastrointestinal disorders were 1.4 times more prevalent among those who had used any chloroquine (n = 63; 9.1%) than among those who had not used any chloroquine (n = 486; 6.7%). When stratified by prolonged exposure to chloroquine, no statistically significant difference in gastrointestinal disorders was found. The limitations of this study, as previously discussed, restricted the committee’s ability to make inferences about any persistent gastrointestinal adverse events of chloroquine use. Based on the available evidence, the committee concludes that there is insuf- ficient or inadequate evidence of an association between the use of chloroquine for malaria prophylaxis and persistent or latent gastrointestinal events. Current evidence does not suggest further study of such an association is warranted, given the lack of evidence regarding biologic plausibility, adverse events associated with concurrent use, or findings from the existing epidemiologic studies. Eye Disorders There are known associations between eye disorders and concurrent use of chloroquine when used at higher doses than the recommended regimen for malaria prophylaxis or when a large cumulative dose is taken over an extended period of time. The FDA label and package insert lists maculopathy, macular degeneration, and retinal damage as potentially irreversible adverse events that may occur as a result of chloroquine use. However, the label also states that this damage usually occurs in individuals who are receiving long-term or high-dosage 4-aminoquinoline therapy, neither of which would typically be the case for individuals, including

346 LONG-TERM HEALTH EFFECTS OF ANTIMALARIAL DRUGS military and veteran populations, using chloroquine for malaria prophylaxis. A systematic review examining the concurrent adverse events associated with malaria prophylaxis in short-term travelers found no statistically significant differences in visual impairment between chloroquine and mefloquine users (Tickell-Painter et al., 2017). The committee identified one published case study in which an individual was diagnosed with chloroquine retinopathy and experienced adverse vision- related symptoms. The individual was using chloroquine for malaria prophylaxis; however, the study states that chloroquine was being used simultaneously to treat a connective tissue disorder, indicating that it is likely the individual was receiving a greater dose of chloroquine than recommended for malaria prophylaxis. Experi- ments conducted in vitro and in animal models indicate that chloroquine’s effects on lysosomal function or its binding to melanin can impair the health and viability of the retinal pigment epithelium. Both actions may underlie the risks to the visual system that are associated with chloroquine treatment, although these are not neces- sarily observed at prophylactic doses. Tan et al. (2017) was the only post-cessation epidemiologic study that pre- sented data on eye disorders; these included macular degeneration, retinopathy, and “any” ophthalmologic disorder. No association between chloroquine use and ocular toxicity was found, although specific data were not reported. Based on the available evidence, the committee concludes that there is insuf- ficient or inadequate evidence of an association between the use of chloroquine for malaria prophylaxis and persistent or latent eye disorders. 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 data from the existing epidemiologic studies. Cardiovascular Disorders Some studies of concurrent adverse events associated with chloroquine use (e.g., Bustos et al., 1994) as well as the FDA labels and package insert, indicate that chloroquine may result in concurrent cardiac adverse events (e.g., hypoten- sion, prolongation of the QTc interval). There is not a substantial body of evidence that addresses the cardiac actions of chloroquine, and indeed it has been suggested that chloroquine’s inhibitory effects on PLA2 may be of benefit in the treatment of arrhythmias (Tobón et al., 2019). In terms of post-cessation epidemiologic studies examining persistent or latent adverse events, only Tan et al. (2017) examined cardiovascular outcomes. The included conditions were arrhythmia, congestive heart failure, myocardial infarc- tion, and “any” cardiac disorder. No association was reported between chloroquine use and any of these conditions when compared with people who did not use chloroquine, but the authors did not report specific frequencies or effect estimates.

CHLOROQUINE 347 Based on the available evidence, the committee concludes that there is insuf- ficient or inadequate evidence of an association between the use of chloroquine for malaria prophylaxis and persistent or latent cardiovascular events. Current evidence does not suggest further study of such an association is warranted, given the lack of evidence regarding biologic plausibility, adverse events associated with concurrent use, or findings from the existing epidemiologic studies. Other Outcomes and Disorders Lege-Oguntoye et al. (1990) examined the immune response among 27 individuals randomly assigned to chloroquine or placebo groups. Three months after these individuals had begun their chloroquine use, investigators found that immunofluorescence assay titers to P. falciparum had declined, and they decreased further throughout the study. The decreased titers persisted for up to 2 months post-chloroquine-cessation. Furthermore, the serum concentrations of IgG and IgM were significantly reduced 2 months after chloroquine withdrawal. These outcomes are considered to be intermediate, and the relevance to clinical outcomes is not clear. Concurrent adverse effects on immune endpoints are evident at one post-cessation time point but not thereafter, and they are in general alignment with a wealth of data demonstrating chloroquine to have anti-inflammatory actions. While these data suggest vulnerability to immune challenges, the results of the study are only weakly supported by other findings (Osorio et al., 1992). Based on this evidence, the committee believed that immune dysfunction is likely not associated with the use of chloroquine for malaria prophylaxis. Tan et al. (2017) also examined dermatologic health outcomes and found no association between persistent adverse dermatologic events and chloroquine use; nevertheless, the committee did identify some weak signals for dermato- logic disorders within the scientific literature. One case study reported a patient with desquamation and symmetrical hypopigmentation of the hands, which fully resolved by 3 months post-chloroquine-cessation. The FDA label and systematic reviews previously discussed in this chapter also list concurrent adverse events of pruritus and the exacerbating effects of chloroquine use on attacks in people with psoriasis; however, these findings were not reported in the included epidemiologic studies. Tan et al. (2017) also examined the associations between chloroquine and a number of additional persistent outcomes, including reproductive, hematologic, and cancer, and found no association. REFERENCES Accapezzato, D., V. Visco, V. Francavilla, C. Molette, T. Donato, M. Paroli, M. U. Mondelli, M. Doria, M. R. Torrisi, and V. Barnaba. 2005. Chloroquine enhances human CD8+ T cell responses against soluble antigens in vivo. J Exp Med 202(6):817-828.

348 LONG-TERM HEALTH EFFECTS OF ANTIMALARIAL DRUGS Aizawa, T., T. Imaizumi, K. Hirono, S. Watanabe, K. Tsugawa, and H. Tanaka. 2019. Chloroquine attenuates TLR3-mediated plasminogen activator inhibitor-1 expression in cultured human glomerular endothelial cells. Clin Exp Nephrol 23(4):448-454. 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. Audo, I., and M. E. Warchol. 2012. Retinal and cochlear toxicity of drugs: New insights into mecha- nisms and detection. Curr Opin Neurol 25(1):76-85. Baird, J. K., D. J. Fryauff, H. Basri, M. J. Bangs, B. Subianto, I. Wiady, Purnomo, B. Leksana, S. Masbar, T. L. Richie, T. R. Jones, E. Tjitra, F. S. Wignall, and S. L. Hoffman. 1995. Prima- quine for prophylaxis against malaria among nonimmune transmigrants in Irian Jaya, Indonesia. Am J Trop Med Hyg 52(6):479-484. Barrett, P. J., P. D. Emmins, P. D. Clarke, and D. J. Bradley. 1996. Comparison of adverse events as- sociated with use of mefloquine and combination of chloroquine and proguanil as antimalarial prophylaxis: Postal and telephone survey of travellers. Br Med J 313(7056):525-528. Berberian, D. A. 1947. Treatment and prophylaxis of malaria with aralen. J Palest Arab Med Assoc 2(6):143-151. Bertagnolio, S., E. Tacconelli, G. Camilli, and M. Tumbarello. 2001. Case report: Retinopathy after malaria prophylaxis with chloroquine. Am J Trop Med Hyg 65(5):637-638. Bijker, E. M., R. Schats, J. M. Obiero, M. C. Behet, G. J. Van Gemert, M. Van De Vegte-Bolmer, W. Graumans, L. Van Lieshout, G. J. H. Bastiaens, K. Teelen, C. C. Hermsen, A. Scholzen, L. G. Visser, and R. W. Sauerwein. 2014. Sporozoite immunization of human volunteers under meflo- quine prophylaxis is safe, immunogenic and protective: A double-blind randomized controlled clinical trial. PLOS ONE 9(11):e112910. Bondeson, J., and R. Sundler. 1998. Antimalarial drugs inhibit phospholipase A2 activation and induc- tion of interleukin 1beta and tumor necrosis factor alpha in macrophages: Implications for their mode of action in rheumatoid arthritis. Gen Pharmacol 30(3):357-366. Boudreau, E. F., L. W. Pang, S. Chaikummao, and C. Witayarut. 1991. Comparison of mefloquine, chloroquine plus pyrimethamine-sulfadoxine (fansidar), and chloroquine as malarial prophy- laxis in eastern Thailand. SE Asian J Trop Med 22(2):183-189. Boudreau, E., B. Schuster, J. Sanchez, W. Novakowski, R. Johnson, D. Redmond, R. Hanson, and L. Dausel. 1993. Tolerability of prophylactic lariam regimens. Trop Med Parasitol 44(3):257-265. Brohult, J., L. Rombo, V. Sirleaf, and E. Bengtsson. 1979. The concentration of chloroquine in serum during short and long term malaria prophylaxis with standard and “double” dosage in non- immunes: Clinical implications. Ann Trop Med Parasitol 73(5):401-405. Brundage, J. 2003. Conserving the fighting strength: Milestones of operational military preventive medicine research. In P. W. Kelley (ed.), Military preventive medicine: Mobilization and de- ployment, Vol. 1. Washington, DC: TMM Publications, Office of the Surgeon General, United States Army. Pp. 105-126. Bunnag, D., S. Malikul, S. Chittamas, D. Chindanond, T. Harinasuta, M. Fernex, M. L. Mittelholzer, S. Kristiansen, and D. Sturchler. 1992. Fansimef for prophylaxis of malaria: A double-blind randomized placebo controlled trial. SE Asian J Trop Med 23(4):777-782. Bustos, M. D., F. Gay, B. Diquet, P. Thomare, and D. Warot. 1994. The pharmacokinetics and elec- trocardiographic effects of chloroquine in healthy subjects. Trop Med Parasitol 45(2):83-86. Cabral, R. T. S., E. M. Klumb, M. I. N. N. Couto, and S. Carneiro. 2019. Evaluation of toxic retinopa- thy caused by antimalarial medications with spectral domain optical coherence tomography. Arq Bras Oftalmol 82(1):12-17. CDC (Centers for Disease Control and Prevention). 2019. Yellow book. https://wwwnc.cdc.gov/travel/ yellowbook/2020/travel-related-infectious-diseases/malaria (accessed September 26, 2019). Cui, G., X. Ye, T. Zuo, H. Zhao, Q. Zhao, W. Chen, and F. Hua. 2013. Chloroquine pretreatment inhibits toll-like receptor 3 signaling after stroke. Neurosci Lett 548:101-104.

CHLOROQUINE 349 Cunningham, J., J. Horsley, D. Patel, A. Tunbridge, and D. G. Lalloo. 2014. Compliance with long- term malaria prophylaxis in British expatriates. Travel Med Infect Dis 12(4):341-348. Dai, C., X. Xiao, D. Li, S. Tun, Y. Wang, T. Velkov, and S. Tang. 2018. Chloroquine ameliorates carbon tetrachloride-induced acute liver injury in mice via the concomitant inhibition of inflam- mation and induction of apoptosis. Cell Death Dis 9(12):1164. Ducharme, J., and R. Farinotti. 1996. Clinical pharmacokinetics and metabolism of chloroquine. Focus on recent advancements. Clin Pharmacokinet 31(4):257-274. Farooqui, A. A., W. Y. Ong, and L. A. Horrocks. 2006. Inhibitors of brain phospholipase A2 activity: Their neuropharmacological effects and therapeutic importance for the treatment of neurologic disorders. Pharmacol Rev 58(3):591-620. FDA (Food and Drug Administration). 2003a. FDA letter, Aralen® chloroquine phosphate, USP package insert. https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview. process&ApplNo=006002 (accessed October 21, 2019). FDA. 2003b. Package insert for Aralen® chloroquine phosphate, USP. https://www.accessdata.fda. gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=006002 (accessed October 21, 2019). FDA. 2009. Package insert for chloroquine phosphate tablets, USP. https://www.accessdata.fda.gov/ scripts/cder/daf/index.cfm?event=overview.process&ApplNo=083082 (accessed October 21, 2019). FDA. 2012. A guide to drug safety terms at FDA. https://www.fda.gov/media/74382/download (ac- cessed July 8, 2019). FDA. 2013. Package insert for Aralen® chloroquine phosphate, USP. https://www.accessdata.fda. gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=006002 (accessed October 21, 2019). FDA. 2017. Package insert for Aralen® chloroquine phosphate, USP. https://www.accessdata.fda. gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=006002 (accessed October 21, 2019). FDA. 2018. Package insert for Aralen® chloroquine phosphate, USP. https://www.accessdata.fda. gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=006002 (accessed October 21, 2019). Ferrucci, S., S. F. Anderson, and J. C. Townsend. 1998. Retinitis pigmentosa inversa. Optom Vis Sci 75(8):560-570. Fox, R. I., and H. I. Kang. 1993. Mechanism of action of antimalarial drugs: Inhibition of antigen processing and presentation. Lupus 2(Suppl 1):S9-S12. Fryauff, D. J., A. L. Richards, J. K. Baird, T. L. Richie, E. Mouzin, E. Tjitra, M. A. Sutamihardja, S. Ratiwayanto, H. Hadiputranto, R. P. Larasati, N. Pudjoprawoto, B. Subianto, and S. L. Hoff- man. 1996. Lymphocyte proliferative response and subset profiles during extended periods of chloroquine or primaquine prophylaxis. Antimicrob Agents Chemother 40(12):2737-2742. Galluzzi, L., J. M. Bravo-San Pedro, B. Levine, D. R. Green, and G. Kroemer. 2017. Pharmacological modulation of autophagy: Therapeutic potential and persisting obstacles. Nat Rev Drug Discov 16(7):487-511. Handschin, J. C., M. Wall, R. Steffen, and D. Sturchler. 1997. Tolerability and effectiveness of malaria chemoprophylaxis with mefloquine or chloroquine with or without co-medication. J Travel Med 4(3):121-127. Harries, A. D., C. J. Forshaw, and H. M. Friend. 1988. Malaria prophylaxis amongst British residents of Lilongwe and Kasungu districts, Malawi. Trans R Soc Trop Med Hyg 82(5):690-692. Harris, L., E. Downar, N. A. Shaikh, and T. Chen. 1988. Antiarrhythmic potential of chloroquine: New use for an old drug. Can J Cardiol 4(6):295-300. He, S., Q. Li, X. Jiang, X. Lu, F. Feng, W. Qu, Y. Chen, and H. Sun. 2018. Design of small molecule autophagy modulators: A promising druggable strategy. J Med Chem 61(11):4656-4687.

350 LONG-TERM HEALTH EFFECTS OF ANTIMALARIAL DRUGS Henderson, A., J. W. Simon, and W. Melia. 1986. Failure of malaria chemoprophylaxis with a ­ roguanil-chloroquine combination in Papua New Guinea. Trans R Soc Trop Med Hyg p 80(5):838-840. Higgins, J. P. T., J. A. Lopez-Lopez, B. J. Becker, S. R. Davies, S. Dawson, J. M. Grimshaw, L. A. McGuinness, T. H. M. Moore, E. A. Rehfuess, J. Thomas, and D. M. Caldwell. 2019. Synthesising quantitative evidence in systematic reviews of complex health interventions. BMJ Glob Health 4(Suppl 1):e000858. Hill, D. R. 2000. Health problems in a large cohort of Americans traveling to developing countries. J Travel Med 7(5):259-266. Hilton, E., B. Edwards, and C. Singer. 1989. Reported illness and compliance in U.S. travelers attend­ ing an immunization facility. Arch Intern Med 149(1):178-179. Huzly, D., C. Schonfeld, W. Beuerle, and U. Bienzle. 1996. Malaria chemoprophylaxis in German tourists: A prospective study on compliance and adverse reactions. J Travel Med 3(3):148-155. Imaizumi, T., R. Hayakari, T. Matsumiya, H. Yoshida, K. Tsuruga, S. Watanabe, S. Kawaguchi, and H. Tanaka. 2017. Chloroquine attenuates TLR3/IFN-beta signaling in cultured normal human mesangial cells: A possible protective effect against renal damage in lupus nephritis. Mod Rheumatol 27(6):1004-1009. Janowsky, A., A. J. Eshleman, R. A. Johnson, K. M. Wolfrum, D. J. Hinrichs, J. Yang, T. M. Zabriskie, M. J. Smilkstein, and M. K. Riscoe. 2014. Mefloquine and psychotomimetics share neurotrans- mitter receptor and transporter interactions in vitro. Psychopharmacology 231(14):2771-2783. Karstorp, A., H. Ferngren, P. Lundbergh, and U. Lying-Tunell. 1973. Letter: Neuromyopathy during malaria suppression with chloroquine. Br Med J 4(5894):736. Kitchen, L. W., D. W. Vaughn, and D. R. Skillman. 2006. Role of U.S. military research programs in the development of US Food and Drug Administration—Approved antimalarial drugs. Clin Infect Dis 43(1):67-71. Kokong, D. D., A. Bakari, and B. M. Ahmad. 2014. Ototoxicity in Nigeria: Why it persists. Ear Nose Throat J 93(7):256-264. Korhonen, C., K. Peterson, C. Bruder, and P. Jung. 2007. Self-reported adverse events associated with antimalarial chemoprophylaxis in Peace Corps volunteers. Am J Prev Med 33(3):194-199. Krishna, S., and N. J. White. 1996. Pharmacokinetics of quinine, chloroquine, and amodiaquine: Clinical implications. Clin Pharmacokinet 30(4):263-299. Labriola, L. T., D. Jeng, and A. A. Fawzi. 2012. Retinal toxicity of systemic medications. Int ­Ophthalmol Clin 52(1):149-166. Lange, W. R., D. L. Frankenfield, M. Moriarty-Sheehan, C. S. Contoreggi, and J. D. Frame. 1994. No evidence for chloroquine-associated retinopathy among missionaries on long-term malaria chemoprophylaxis. Am J Trop Med Hyg 51(4):389-392. Lat, I., D. R. Foster, and B. Erstad. 2010. Drug-induced acute liver failure and gastrointestinal com- plications. Crit Care Med 38(6 Suppl.):S175-S187. Laverone, E., S. Boccalini, A. Bechini, S. Belli, M. G. Santini, S. Baretti, G. Circelli, F. Taras, S. Banchi, and P. Bonanni. 2006. Travelers’ compliance to prophylactic measures and behavior during stay abroad: Results of a retrospective study of subjects returning to a travel medicine center in Italy. J Trav Med 13(6):338-344. Lege-Oguntoye, L., G. C. Onyemelukwe, B. B. Maiha, E. O. Udezue, and S. Eckerbom. 1990. The effect of short-term malaria chemoprophylaxis on the immune response of semi-immune adult volunteers. East Afr Med J 67(11):770-778. Liu, L., Y. Katz, R. Weizman, B. Rosenberg, G. W. Pasternak, and M. Gavish. 1991. Interactions of chloroquine with benzodiazepine, gamma-aminobutyric acid and opiate receptors. Biochem Pharmacol 41(10):1534-1536. Lobel, H. O., K. W. Bernard, S. L. Williams, A. W. Hightower, L. C. Patchen, and C. C. Campbell. 1991. Effectiveness and tolerance of long-term malaria prophylaxis with mefloquine. Need for a better dosing regimen. JAMA 265(3):361-364.

CHLOROQUINE 351 Lobel, H. O., M. Miani, T. Eng, K. W. Bernard, A. W. Hightower, and C. C. Campbell. 1993. Long- term malaria prophylaxis with weekly mefloquine. Lancet 341(8849):848-851. Maier, J. 1948. A field trial of chloroquine (SN 7618) as a suppressive against malaria in the ­Philippines. Am J Trop Med Hyg 28(3):407-412. McGready, R., K. L. Thwai, T. Cho, L. S. Samuel, N. J. White, and F. Nosten. 2002. The effects of quinine and chloroquine antimalarial treatments in the first trimester of pregnancy. Trans R Soc Trop Med Hyg 96(2):180-184. Meier, C. R., K. Wilcock, and S. S. Jick. 2004. The risk of severe depression, psychosis or panic attacks with prophylactic antimalarials. Drug Saf 27(3):203-213. Moore, B. R., and T. M. E. Davis. 2018. Pharmacotherapy for the prevention of malaria in pregnant women: Currently available drugs and challenges. Expert Opin Pharmacother 19(16):1779-1796. Mulhauser, P., Y. Allemann, and C. Regamey. 1995. Chloroquine and nonconvulsive status ­ pilepticus. e Ann Intern Med 123(1):76-77. Munera, Y., F. C. Hugues, C. Le Jeunne, and J. F. Pays. 1997. Interaction of thyroxine sodium with antimalarial drugs. BMJ 314(7094):1593. Osorio, L. M., L. Fonte, and C. M. Finlay. 1992. Inhibition of human monocyte function by prophy- lactic doses of chloroquine. Am J Trop Med Hyg 46(2):165-168. Park, J. S., K. S. Choi, E. J. Jeong, D. H. Kwon, E. N. Benveniste, and C. H. Choi. 2004. Reactive oxygen species mediate chloroquine-induced expression of chemokines by human astroglial cells. Glia 47:9-20. Peragallo, M. S., G. Sabatinelli, and G. Sarnicola. 1999. Compliance and tolerability of mefloquine and chloroquine plus proguanil for long-term malaria chemoprophylaxis in groups at particular risk (the military). Trans R Soc Trop Med Hyg 93(1):73-77. Petersen, E., T. Ronne, A. Ronn, I. Bygbjerg, and S. O. Larsen. 2000. Reported side effects to chloro­ quine, chloroquine plus proguanil, and mefloquine as chemoprophylaxis against malaria in Danish travelers. J Travel Med 7(2):79-84. Physicians Desk Reference, 44th ed. 1990. Medical Economics Company. Pp. 2305-2306. Picot, S., F. Peyron, A. Donadille, J. P. Vuillez, G. Barbe, and P. Ambroise-Thomas. 1993. Chloro- quine-induced inhibition of the production of TNF, but not of IL-6, is affected by disruption of iron metabolism. Immunology 80(1):127-133. Public Health England. 2018. Guidelines for malaria prevention in travelers from the UK. https:// assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/ file/774781/ACMP_guidelines_2018.pdf (accessed December 7, 2019). Rimpela, A. K., M. Reinisalo, L. Hellinen, E. Grazhdankin, H. Kidron, A. Urtti, and E. M. del Amo. 2018. Implications of melanin binding in ocular drug delivery. Adv Drug Deliv Rev 126:23-43. Roestenberg, M., M. McCall, J. Hopman, J. Wiersma, A. J. F. Luty, G. J. Van Gemert, M. Van De Vegte-Bolmer, B. Van Schaijk, K. Teelen, T. Arens, L. Spaarman, Q. De Mast, W. Roeffen, G. Snounou, L. Renia, A. Van Der Ven, C. C. Hermsen, and R. Sauerwein. 2009. Protection against a malaria challenge by sporozoite inoculation. N Engl J Med 361(5):468-477. Roestenberg, M., A. C. Teirlinck, M. B. B. McCall, K. Teelen, K. N. Makamdop, J. Wiersma, T. Arens, P. Beckers, G. Van Gemert, M. Van De Vegte-Bolmer, A. J. A. M. Van Der Ven, A. J. F. Luty, C. C. Hermsen, and R. W. Sauerwein. 2011. Long-term protection against malaria after experimental sporozoite inoculation: An open-label follow-up study. Lancet 377(9779):1770-1776. Salako, L. A., R. A. Adio, O. Walker, A. Sowunmi, D. Sturchler, M. L. Mittelholzer, R. Reber-Liske, and U. Dickschat. 1992. Mefloquine-sulphadoxine-pyrimethamine (fansimef, Roche) in the pro- phylaxis of Plasmodium falciparum malaria: A double-blind, comparative, placebo-controlled study. Ann Trop Med Parasitol 86(6):575-581. Salman, S., F. Baiwog, M. Page-Sharp, K. Kose,  H. A. Karunajeewa,  I. Mueller,  S. J. Rogerson,  P. M. Siba, K. F. Ilett, and T. M. E. Davis. 2017. Optimal antimalarial dose regimens for chlo- roquine in pregnancy based on population pharmacokinetic modelling. Int J Antimicrob Agents 50(4):542-551.

352 LONG-TERM HEALTH EFFECTS OF ANTIMALARIAL DRUGS Schlagenhauf, P., M. E. Wilson, E. Petersen, A. McCarthy, L. H. Chen, J. S. Keystone, P. E. Kozarsky, B. A. Connor, H. D. Nothdurft, M. Mendelson, and K. Leder. 2019. Malaria chemoprophylaxis. J Travel Med 4(15):145-167. Schneider, C., M. Adamcova, S. S. Jick, P. Schlagenhauf, M. K. Miller, H. G. Rhein, and C. R. Meier. 2013. Antimalarial chemoprophylaxis and the risk of neuropsychiatric disorders. Travel Med Infect Dis 11(2):71-80. Schneider, C., M. Adamcova, S. S. Jick, P. Schlagenhauf, M. K. Miller, H. G. Rhein and C. R. Meier. 2014. Use of anti-malarial drugs and the risk of developing eye disorders. Travel Med Infect Dis 12(1):40-47. Schneiderman, A. I., Y. S. Cypel, E. K. Dursa, and R. M. Bossarte. 2018. Associations between use of antimalarial medications and health among U.S. veterans of the wars in Iraq and Afghanistan. Am J Trop Med Hyg 99(3):638-648. Shanks, G. D., M. D. Edstein, R. K. Kereu, P. E. Spicer, and K. H. Rieckmann. 1993. Postexposure administration of halofantrine for the prevention of malaria. Clin Infect Dis 17(4):628-631. Sharafeldin, E., D. Soonawala, J. P. Vandenbroucke, E. Hack, and L. G. Visser. 2010. Health risks encountered by Dutch medical students during an elective in the tropics and the quality and comprehensiveness of pre- and post-travel care. BMC Med Educ 10:89. Sossouhounto, R. T., B. N. Soro, A. Coulibaly, M. L. Mittelholzer, D. Stuerchler, and L. Haller. 1995. Mefloquine in the prophylaxis of P. falciparum malaria. J Travel Med 2(4):221-224. Spira, A. M. 1997. Hypopigmentation and desquamation as dermatologic reactions to aralen. J Travel Med 4(4):189-191. Steffen, R., R. Heusser, R. Machler, R. Bruppacher, U. Naef, D. Chen, A. M. Hofmann, and B. Somaini. 1990. Malaria chemoprophylaxis among European tourists in tropical Africa: Use, adverse reactions, and efficacy. Bull WHO 68(3):313-322. Steffen, R., E. Fuchs, J. Schildknecht, U. Naef, M. Funk, P. Schlagenhauf, P. Phillips-Howard, C. Nevill, and D. Sturchler. 1993. Mefloquine compared with other malaria chemoprophylactic regimens in tourists visiting east Africa. Lancet 341(8856):1299-1303. Stemberger, H., R. Leimer, and G. Wiedermann. 1984. Tolerability of long-term prophylaxis with Fansidar: A randomized double-blind study in Nigeria. Acta Tropica 41(4):391-399. Sturchler, D., M. Schar, and N. Gyr. 1987. Leucopenia and abnormal liver function in travelers on malaria chemoprophylaxis. J Trop Med Hyg 90(5):239-243. Tan, K. R., S. J. Henderson, J. Williamson, R. W. Ferguson, T. M. Wilkinson, P. Jung, and P. M. Arguin. 2017. Long term health outcomes among returned Peace Corps volunteers after malaria prophylaxis, 1995–2014. Travel Med Infect Dis 17:50-55. Tegner, R., F. M. Tome, P. Godeau, F. Lhermitte, and M. Fardeau. 1988. Morphological study of peripheral nerve changes induced by chloroquine treatment. Acta Neuropathol 75(3):253-260. Tickell-Painter, M., N. Maayan, R. Saunders, C. Pace, and D. Sinclair. 2017. Mefloquine for prevent- ing malaria during travel to endemic areas. Cochrane Database Syst Rev 10:CD006491. Tobón, C., L. Palacio, B. Chidipi, D. P. Slough, T. Tran, N. Tran, M. Reiser, Y. Lin, B. Herweg, D. Sayad, J. Saiz, and S. Noujaim. 2019. The antimalarial chloroquine reduces the burden of persistent atrial fibrillation. Front Pharmacol doi:10.3389/fphar.2019.01392. Villegas, L., R. McGready, M. Htway, M. K. Paw, M. Pimanpanarak, R. Arunjerdja, S. J. ­ iladpai-Nguen, V B. Greenwood, N. J. White, and F. Nosten. 2007. Chloroquine prophylaxis against vivax ­malaria in pregnancy: A randomized, double-blind, placebo-controlled trial. Trop Med Int Health 12(2):209-218. Waner, S., D. Durrhiem, L. E. Braack, and S. Gammon. 1999. Malaria protection measures used by in-flight travelers to South African game parks. J Trav Med 6(4):254-257. White, N. J. 1985. Clinical pharmacokinetics of antimalarial drugs. Clin Pharmacokin 10(3):187-215. Winkler, W. P. 1970. The successful control of malaria in the 173d Airborne Brigade. Mil Med 135(2):107-111.

CHLOROQUINE 353 Woehrling, E. K., E. J. Hill, and M. D. Coleman. 2010. Evaluation of the importance of astrocytes when screening for acute toxicity in neuronal cell systems. Neurotox Res 17(2):103-113. Wolfe, M. S., and J. F. Cordero. 1985. Safety of chloroquine in chemosuppression of malaria during pregnancy. Br Med J Clin Res 290(6480):1466-1467. Yax, J. A., C. D. Collins, and P. N. Malani. 2007. Prevention and prophylaxis of malaria in older travelers. Clin Geriatr 15(8):36-45.

Next: 10 Improving the Quality of Research on the Long-Term Health Effects of Antimalarial Drugs »
Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis Get This Book
×
Buy Paperback | $90.00
MyNAP members save 10% online.
Login or Register to save!
Download Free PDF

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

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

  1. ×

    Welcome to OpenBook!

    You're looking at OpenBook, NAP.edu's online reading room since 1999. Based on feedback from you, our users, we've made some improvements that make it easier than ever to read thousands of publications on our website.

    Do you want to take a quick tour of the OpenBook's features?

    No Thanks Take a Tour »
  2. ×

    Show this book's table of contents, where you can jump to any chapter by name.

    « Back Next »
  3. ×

    ...or use these buttons to go back to the previous chapter or skip to the next one.

    « Back Next »
  4. ×

    Jump up to the previous page or down to the next one. Also, you can type in a page number and press Enter to go directly to that page in the book.

    « Back Next »
  5. ×

    To search the entire text of this book, type in your search term here and press Enter.

    « Back Next »
  6. ×

    Share a link to this book page on your preferred social network or via email.

    « Back Next »
  7. ×

    View our suggested citation for this chapter.

    « Back Next »
  8. ×

    Ready to take your reading offline? Click here to buy this book in print or download it as a free PDF, if available.

    « Back Next »
Stay Connected!