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5 Tafenoquine Tafenoquine, an 8-aminoquinoline, was discovered in 1978 by the Walter Reed Army Institute of Research during a search for a safer, more effective, and longer-acting drug than primaquine (Ebstie et al., 2016; Shanks and Edstein, 2005). The institute partnered with GlaxoSmithKline and Medicines for Malaria Venture to develop the drug (Ebstie et al., 2016). In July 2018 the Food and Drug Administration (FDA) new drug application for Krintafelâ¢ (tafenoquine 150 mg tablet) submitted by GlaxoSmithKline was approved for the radical cure (preven- tion of relapse) of Plasmodium vivax malaria in people receiving therapy for acute P. vivax infection (FDA, 2018a). In August 2018 FDA approved the new drug application submitted by 60 Degrees Pharmaceuticals for Arakodaâ¢ (tafenoquine 100 mg tablet) for malaria prophylaxis for up to 6 months of continuous use in people aged 18 years and older (FDA, 2018b). The Arakodaâ¢ approval was granted under FDAâs priority review, an accelerated evaluation process for drugs that potentially offer significant improvements in the safety or effectiveness of a treatment or preventive agent when compared with standard applications (FDA, 2018c). The two drugs have the same composition but different formulations and indications; as malaria prophylaxis is the focus of the committeeâs assessment, its focus is on only Arakodaâ¢. The three-decade lag between the drugâs discovery and FDA approval has been attributed to tafenoquine being discovered at a time when less attention was paid to antimalarial drug development; in recent years, recognition of the global health implications of malaria has spurred development efforts (Baird, 2018). Tafenoquine has activity against all pre-erythrocytic (liver) and erythrocytic (blood) stages of the Plasmodium species, including P. falciparum and P. vivax. Thus, like primaquine, it can be used as primary prophylaxis while in an endemic 177
178 LONG-TERM HEALTH EFFECTS OF ANTIMALARIAL DRUGS region, and it is also effective post-exposure (toward the end of or after a stay in an endemic region) for prophylactic presumptive anti-relapse therapy (PART), also called âterminal prophylaxis,â owing to its ability to eliminate the hypnozoites of P. falciparum and P. vivax (FDA, 2018c). Hypnozoites, which are undetectable by diagnostic tests, can lie dormant in the liver for months to years and then dif- ferentiate, causing clinical malaria and enabling malaria transmission (Ackert et al., 2019; Rishikesh and Sarava, 2016). The FDA-approved malaria-prophylaxis regimen for tafenoquine is a loading dose of 200 mg (2 Ã 100 mg tablet) once daily for 3 days before travel to a malaria-endemic area, followed by a maintenance dose of 200 mg once weekly while in the malaria area, followed by one 200 mg dose 7 days after the last maintenance dose (FDA, 2018d); this dosage is also recommended by the Centers for Disease Control and Prevention (Haston et al., 2019). Studies of other drugs for malaria prophylaxis in U.S. soldiers suggest that antimalarials with a weekly regimen may yield higher adherence rates than regi- mens requiring more frequent dosing (SÃ¡nchez et al., 1993; Saunders et al., 2015). Because tafenoquine is a newly approved drug, published data containing information on adverse effects are limited compared with what is available for drugs that have been in use longer. In an effort to include any data that might inform its understanding of adverse effects that could be associated with the use of tafenoquine, the committee reviewed certain types of evidence that were not included in other drug chapters; the reasoning for each inclusion will be addressed in the section in which the evidence appears. This chapter begins with information from the tafenoquine package insert and label, with emphasis on the Contraindica- tions and Warnings, Precautions, and Drug Interactions sections. This is followed by summaries of findings and conclusions regarding the use of tafenoquine in military forces as reported by U.S. and foreign governments. The pharmacokinetic properties of tafenoquine are then described before a summary of the known con- current adverse events associated with use of tafenoquine when used as directed for prophylaxis. Most of the chapter is dedicated to summarizing and assessing the seven identified epidemiologic studies that contributed some information on persistent or latent health outcomes following cessation of tafenoquine. These are ordered by population, with studies of military and veterans first, followed by studies with research volunteers. A table that gives a high-level comparison of each of the seven epidemiologic studies that examined the use of tafenoquine and that met the committeeâs inclusion criteria is presented in Appendix C. Supplemental supporting evidence is then presented, beginning with other identified studies of health outcomes in populations that used tafenoquine for prophylaxis but that did not meet the committeeâs inclusion criteria regarding the timing of follow-up, fol- lowed by case reports of persistent adverse events associated with tafenoquine use and adverse events findings from treatment trials. Information on adverse events associated with tafenoquine use in specific groups, including women and women who are pregnant, is presented. After the primary and supplemental evidence in humans has been presented, supporting literature from experimental animal and
TAFENOQUINE 179 in vitro studies is then summarized. The chapter ends with a synthesis of all of the evidence presented along with the inferences and conclusions that the committee made from the available evidence, organized by health outcome category. FOOD AND DRUG ADMINISTRATION PACKAGE INSERT FOR TAFENOQUINE This section describes selected information found in the FDA label or pack- age insert for tafenoquine (Arakodaâ¢); since tafenoquine was approved in 2018, FDA has issued only one label. The information from the insert is followed by a brief synopsis of drug interactions known or presumed to occur with concurrent tafenoquine use. Contraindications, Warnings, and Precautions The FDA package insert states that in five clinical prophylaxis trials in which participants received the FDA-approved tafenoquine loading and maintenance dosing regimen (200 mg for 3 days, followed by 200 mg weekly) (n = 825), the most common âselectedâ adverse reactions (incidence â¥1%) were headache, diz- ziness, back pain, diarrhea, nausea, vomiting, increased alanine aminotransferase, motion sickness, insomnia, depression, abnormal dreams, and anxiety (FDA, 2018d). These five clinical trials are referred to in this section as the âsafety set.â According to the FDA package insert, contraindications to tafenoquine include glucose-6-phosphate dehydrogenaseÂ (G6PD) deficiency (see Chapter 2) or unknown G6PD status, due to the risk of hemolytic anemia, and breastfeeding by a lactating woman when the infant is found to be G6PD deficient or if the G6PD status of the infant is unknown (FDA, 2018d). Tafenoquine should be adminis- tered only to those with a safe level of G6PD activity (see Chapter 2). If severe hemolytic anemia is not treated or controlled, it can lead to serious complications, including arrhythmias, cardiomyopathy,Â heart failure, and death (Baird, 2019; NIH, n.d.). Qualitative G6PD tests are sufficient to diagnose G6PD deficiency in males, but quantitative G6PD testing is necessary to differentiate G6PD statuses (deficient, intermediate, normal) in females (Chu et al., 2018). Testing for G6PD deficiency is mandatory before prescribing tafenoquine (FDA, 2018d). Because tafenoquine is contraindicated with G6PD deficiency, the committee did not review this adverse event in depth. A history of psychotic disorders or current psychotic symptoms (i.e., hal- lucinations, delusions, or grossly disorganized behavior) is a contraindication for tafenoquine (FDA, 2018d). Users are also warned that because of the long half- life of tafenoquine (approximately 17 days), the signs or symptoms of psychiatric adverse reactions could be delayed in onset or duration. The FDA package insert states, âIf psychotic symptoms (hallucinations, delusions, or grossly disorganized
180 LONG-TERM HEALTH EFFECTS OF ANTIMALARIAL DRUGS thinking or behavior) occur, consider discontinuation of Arakodaâ¢ and prompt evaluation by a mental health professional as soon as possible. Other psychiatric symptoms, such as changes in mood, anxiety, insomnia, and nightmares, should be promptly evaluated by a medical professional if they are moderate and last more than three days or are severe.â The package insert notes that psychiatric adverse reactions in participants receiving tafenoquine in clinical trials included sleep dis- turbances (2.5%), depression/depressed mood (0.3%), and anxiety (0.2%), and that tafenoquine was discontinued in one participant who attempted suicide (0.1%); however, the source of these data is not cited. Known hypersensitivity reactions to tafenoquine, other 8-aminoquinolines, or any component of tafenoquine (FDA, 2018d) are also a contraindication. The FDA package insertâs Warnings and Precautions section alerts against contraindication- associated conditions and disorders as well as methemoglobinemia and further warns that because of tafenoquineâs long half-life, hemolytic anemia, methemo- globinemia, and signs or symptoms of hypersensitivity reactions that may occur could be delayed in onset or duration. Tafenoquine is associated with methemoglobinemia; persons with nicotin- amide adenine dinucleotide (NADH)-dependent methemoglobin reductase defi- ciency should be monitored and should stop the drug and seek medical attention if signs of methemoglobinemia occur (FDA, 2018d). Methemoglobinemia results from increased levels of methemoglobin (>1%) in red blood cells, which can result in decreased availability of oxygen to tissues (Denshaw-Burke et al., 2018). High levels of methemoglobin (>15%) can lead to complications, including abnormal cardiac rhythms, altered mental status, delirium, seizures, coma, and profound acidosis; if the levels exceed 70%, death can occur. Methemoglobinemia, which is usually mild and reversible, is a well-charac- terized feature in recipients of 8-aminoquinolines at therapeutic dosing (Baird, 2019). Tafenoquine is associated with decreases in hemoglobin, and decreases â¥3 g/dL were observed in 2.3% of tafenoquine recipients in the safety set (FDA, 2018d). The package insert notes that in the safety set, symptomatic elevations in methemoglobin occurred in 13% of tafenoquine recipients and hemoglobin decreases â¥3 g/dL occurred in 2.3%. However, no additional information is pro- vided on what the starting or ending hemoglobin values were or whether they were outside of the normal hemoglobin ranges. The âhypersensitivity reactionsâ referred to in the FDA package insertâs Contraindications and Warnings/Precautions sections are not defined other than by referring to urticaria and angioedema as two examples and directing the reader to the â6.1. Clinical Trials Experienceâ section (FDA, 2018d). Section 6.1 pro- vides data based on six trials: the safety set trials and one additional trial (NCT #01290601) in which participants received 400 mg of tafenoquine for 3 days to treat P. vivax (NIH, 2018). No adverse events are characterized as âhypersen- sitivity reactionsâ; âhypersensitivityâ is listed as an adverse reaction within the
TAFENOQUINE 181 category âImmune system disordersâ among adverse reactions reported by <1% in the five prophylaxis trials. The FDA package insert reported that in a pooled analysis of four of the five safety set trials (Hale et al., 2003; Leary et al., 2009; Shanks et al., 2001; Study 030, unpublished), the incidence of diarrhea was 5% in tafenoquine recipients, compared with 1% in mefloquine recipients and 3% in placebo recipients (FDA, 2018d). Serious gastrointestinal adverse events included one participant each with abdominal pain, diarrhea, upper abdominal pain, and irritable bowel syndrome. The package insert (FDA, 2018d) states that vortex keratopathy1 was reported in 21â93% of tafenoquine recipients in three trials that included ophthalmic evaluations (Leary et al., 2009; Nasveld et al., 2010; NCT #0129060, a malaria treatment trial). The label notes further that the vortex keratopathy did not result in functional visual changes and resolved within 1 year of drug cessation, that retinal abnormalities occurred in less than 1% of the tafenoquine recipients, and that seven serious ocular adverse reactions were reported (five vortex keratopathy; two retinal disorders). The FDA package insert also mentions other adverse events. It states that, based on a study of healthy adults who were administered 400 mg tafenoquine (twice the recommended dose for prophylaxis) for 3 days, the mean increase in the QTcF2 interval for tafenoquine is less than 20 ms (FDA, 2018d). It states that the effects of tafenoquine have not been studied in people with renal or hepatic impairment (FDA, 2018d). In addition, FDA required that pharmacists provide a medication guideâa paper handout that conveys risk information that is specific to a particular drug or drug classâto persons to whom tafenoquine is dispensed (FDA, 2012, 2018b). The medication guide alerts consumers to the most important information about a drug, including serious side effects. For tafenoquine (Arakodaâ¢), these serious side effects include hemolytic anemia, methemoglobinemia, and mental health symptoms (FDA, 2018d). 1â Vortex keratopathyÂ manifests as a whorl-like pattern of deposits in the inferior interpalpebral por- tion of the cornea. Certain medications bind with the cellular lipids of the basal epithelial layer of the cornea due to their cationic, amphiphilic properties. It is rare for these deposits to result in a reduction in visual acuity or ocular symptoms, although this has occurred. The deposits typically resolve with discontinuation of the medications (AAO, 2019). 2â The QT interval is a measure of the duration of ventricular repolarization, approximating the time interval between the start and end of repolarization of the ventricular myocardium.Â QT prolongation is associated with a risk for cardiac arrhythmias because it can lead to early-after depolarizations, provoke Torsades des Pointes, and lead to ventricular fibrillation, resulting in sudden cardiac death. A corrected QT is QTc. QTcF refers to a QT interval corrected using the Fridericia formula (Van- denberk et al., 2016).
182 LONG-TERM HEALTH EFFECTS OF ANTIMALARIAL DRUGS Drug Interactions Tafenoquine inhibited metformin transport via human organic cation trans- porter-2 (OCT2), multidrug and toxin extrusion-1 (MATE1), and MATE2-K transporters (FDA, 2018d). The effect of co-administration of tafenoquine on the pharmacokinetics of OCT2 and MATE1 substrates in humans is unknown (FDA, 2018c). In vitro studies show a potential for increased concentrations of OCT2 and MATE substrates that may increase the risk of toxicity of these drugs. Co-administration with OCT2 and MATE substrates should be avoided. Among these drugs are the antidiabetic metformin; gastroesophageal proton-pump inhibi- tors (e.g., cimetidine, ranitidine); antivirals (e.g., lamivudine); the antiarrhythmic, dofetilide; and chemotherapeutics (e.g., cisplatin, oxaliplatin). POLICIES AND INQUIRIES RELATED TO THE USE OF TAFENOQUINE BY MILITARY FORCES A December 2019 Department of Defense (DoD) Defense Health Agency document outlines policy for the force health protection use of tafenoquine for malaria prophylaxis in U.S. service members (DoD, 2019). The issuance states that tafenoquine âis an acceptable alternative medicationâ for primary prophy- laxis in areas where chloroquine-sensitive malaria is present if intolerance or contraindications to chloroquine, atovaquone/proguanil (A/P), and doxycycline are documented; similarly, âit may be consideredâ in areas where chloroquine- resistant malaria is present for those with contraindications or intolerance to A/P and doxycycline. The dosage is 200 mg once daily for 3 days before entering a malaria-endemic area, 200 mg weekly as a maintenance regimen, and one 200 mg dose 7 days after the last maintenance dose. The policy instructs that testing for G6PD deficiency is mandatory for personnel deploying to areas requiring tafenoquine or primaquine. As tafenoquine is an FDA-approved drug, military health-system providers are permitted to prescribe it to service members on an individualized basis.3 In addition to being effective against all stages of all Plas- modium species, an effective hypnozoiticide is of particular value to the U.S. military because P. vivax is endemic in Southeast Asia (CDC, 2019; Howes et al., 2016), where military operations occur. Examples include Afghanistan, where P. vivax represents 95% of malaria cases, and Iraq, where the 1991 Gulf War led to a years-long resurgence of P. vivax (CDC, 2019; Schlagenhauf, 2003). The Australian Senate performed an investigation into the possible association of tafenoquine with adverse effects, particularly neuropsychiatric effects, when used for malaria prophylaxis by its military forces (Australia, 2018). Because 3â Personal communications to the committee, COL Andrew Wiesen, M.D., M.P.H., Director, Preventive Medicine, Health Readiness Policy, and Oversight, Office of the Assistant Secretary of Defense (Health Affairs), April 16, 2019, and December 11, 2019.
TAFENOQUINE 183 tafenoquine was not approved for use as malaria prophylaxis by the Australian Therapeutic Goods Administration until September 2018 (ATGA, 2019), Â tudies s of tafenoquine were conducted as clinical trials in Australian military service members from as early as 1998 (Nasveld et al., 2002). As part of its inquiry, the Australian Senate commissioned a literature review on the impact of quinoline antimalarials and a research study that involved a re-analysis of health study data on antimalarial use from the 2007â2008 Centre for Military and Veteransâ Health deployment-health studies (Australia, 2018). It heard or reviewed submitted testi- mony from government agencies (Department of Defence, Department of Health, Department of Veteransâ Affairs, Australian Defence Force Malaria and Infectious Disease Institute, Indo-Pacific Centre for Health Security, Department of Foreign Affairs and Trade Repatriation Medical Authority); malaria-control organiza- tions (Asia Pacific Leaders Malaria Alliance); professional medical associations (Â ustralasian Society for Infectious Diseases, Australasian College of Tropical A Medicine, Royal Australian College of General Practitioners); advocate organiza- tions (Australian Quinoline Veterans and Families Association, Quinism Founda- tion, Defence Force Welfare Association, Royal Australian Regiment Corporation, RSL National); product development partnerships, pharmaceutical manufacturers, and their partner organizations (Medicines for Malaria Venture, National Health and Medical Research Council, Biocelect, GlaxoSmithKline, 60 Degrees Pharma- ceuticals, Roche); and roughly 25 individuals, including physicians, academics, and veterans. In submitted testimony, a collection of adverse events (psychiatric disorders, cognitive impairments, hearing problems, vestibular disorders, neuro- logic disorders) reported to be due to the use of tafenoquine was referred to as âquinoline poisoningâ and âan acquired brain injuryâ by the Australian Quinoline Veterans and Families Association, and as âchronic quinoline encephalopathyâ or âneuropsychiatric quinismâ by the U.S.-based Quinism Foundation. Some vet- erans attributed their symptoms to tafenoquine use that had occurred 15 or more years before (Australia, 2018). In the report summary, however, the Senate com- mittee did not agree with these claims. While the committee acknowledged that its members were not medical experts, it stated, âThe weight of prevailing medical evidence provided to the committee in response to these claims is that â¦ there is no compelling evidence that tafenoquine causes long term effectsâ and explained that the committee had been informed that there was no definitive evidence to support the claim that tafenoquine use results in acquired brain injury. It stated that while it believed that the symptoms were being experienced by individuals, assigning a single cause to these illnesses did not take into account the multiple possible contributors to their health while they took the drug and in the years after. The committee recommended that the Australian Department of Veteransâ Affairs expedite its investigation into antimalarial claims logged since September 2016 and that it offer assistance to claimants and facilitate their access to legal representation. The Australian Senate committee also made recommendations to ensure better access to care for sick veterans, including that the Australian Depart-
184 LONG-TERM HEALTH EFFECTS OF ANTIMALARIAL DRUGS ment of Veteransâ Affairs prioritize developing a neurocognitive health program. It did not recommend that changes be made to military policy on antimalarial use. Tafenoquine can be prescribed for malaria prevention (under the name Kodatefâ¢) to Australian service members (Australia, n.d.). PHARMACOKINETICS Tafenoquine is an antimalarial drug of the 8-aminoquinoline class, a syn- thetic analog of primaquine (Brueckner et al., 1998). It is a prodrug that requires activation through metabolism by CYP2D6 (Marcsisin et al., 2014). However, little metabolism was observed in vitro in human liver microsomes and hepato- cytes (FDA, 2018d). The major route(s) of excretion of tafenoquine in humans is unknown. In healthy adults taking tafenoquine once daily for 3 days, unchanged tafenoquine was the only notable drug-related component observed in plasma at approximately 3 days after the first dose. In a population pharmacokinetics study (Charles et al., 2007), tafenoquine concentrations were 321 Â± 63 ng/mL when measured within 5% of the time of the estimated mean population Tmax of 21.4 h in individuals given the clinically recom- mended 200 mg weekly dose of tafenoquine. The elimination half-life is approxi- mately 14â17 days (Castelli et al., 2010; Edstein et al., 2001a,b; FDA, 2018d). Food appears to increase the amount but not the rate of tafenoquine absorption, and it has been suggested that the bioavailability of tafenoquine increases with a high-fat meal (Edstein et al., 2001b). In the majority of the clinical trials reviewed for FDA drug approval, tafenoquine was administered under fed conditions (FDA, 2018c). The FDA package insert states that the pharmacoÂ inetics of tafenoquine k were not significantly affected by age, sex, ethnicity, or body weight (FDA, 2018d). The effect of renal or hepatic impairment on tafenoquine pharmacoÂ kinetics is not known. ADVERSE EVENTS This section begins with a summary of the known concurrent adverse effects, such as those that occur immediately or within a few hours or days of taking a dose of tafenoquine. This information is derived from the FDA package insert, the FDA briefing document on tafenoquine, and an integrated safety analysis. Epidemiologic studies of persistent or latent health effects in which information was available at least 28 days post-tafenoquine-cessation are then summarized by population category (military or veterans, and research populations recruited for safety studies) with the emphasis of reported results being on those persistent or latent effects that were associated with use of tafenoquine (even if results on other antimalarial drug comparison groups were presented).
TAFENOQUINE 185 Concurrent Adverse Events The committee was unable to identify any Cochrane reviews examining concurrent adverse events associated with tafenoquine when used for malaria prophylaxis. In an effort to include useful data, the committee reviewed and sum- marized information from the FDA briefing document on tafenoquine, which was prepared by FDA for panel members of the Antimicrobial Drugs Advisory Com- mittee (FDA, 2018c) and contained a safety summary. In addition, an integrated safety analysis is summarized. FDA Briefing Document Data from five clinical trials in which tafenoquine recipients received FDA- approved prophylactic loading and maintenance dosages are presented both in the FDA package insert and in the FDA briefing document (FDA, 2018c,d). As before, this data set will be referred to as the safety set. The safety set included Nasveld et al. (2010), which compared tafenoquine with mefloquine in deployed Australian soldiers; Hale et al. (2003) and Study 030 (unpublished), which com- pared tafenoquine with mefloquine and placebo in residents of Ghana and Kenya, respectively; and Leary et al. (2009) and Shanks et al. (2001), which compared tafenoquine with placebo in U.S. and UK residents, and in residents of malaria- endemic Kenya, respectively (FDA, 2018c,d). For the analyses of the safety set, no formal hypothesis testing was noted, and no statistical comparisons were provided. Neither the package insert nor the FDA briefing document specify the timing of the adverse events summarized below. The FDA briefing document noted that systematic monitoring for neurologic symptoms, such as actively asking participants about symptoms, was not per- formed for the safety set trials. In an analysis of the safety set (tafenoquine group, n = 825), the incidence of headache and lethargy, respectively, were similar between the tafenoquine group (29% and 3%) and the mefloquine group (30% and 4%), and the incidence of dizziness and vertigo/tinnitus, respectively, were lower in the tafenoquine group (3% and 5%) than in the mefloquine group (6% and 7%) (FDA, 2018c). One study in the safety set, which included deployed Australian soldiers (Nasveld et al., 2010), reported the incidence of dizziness, myalgia, and deafness to be similar in the tafenoquine (1.4%, 0.6%, and 0%, respectively) and mefloquine (1.2%, 0.6%, and 0.6%) groups. In the same study, incidence was reported to be lower in the tafenoquine group than in the mefloquine group for headache (14.6% versus 18.5%), fatigue and lethargy (5.7% versus 6.8%), and vertigo/tinnitus (4.9% versus 6.8%) (FDA, 2018c). In a pooled analysis (the methods of which were not specified) of three stud- ies from the safety set that had a similar duration of exposure (12â15 weeks) and that included tafenoquine (n = 252), mefloquine (n = 147), and placebo (n = 256)
186 LONG-TERM HEALTH EFFECTS OF ANTIMALARIAL DRUGS groups, there was a higher incidence of the grouped outcomes of falls, dizziness, and lightheadedness with tafenoquine (5.2%) and mefloquine (10.2%) than with placebo (3.1%); the incidence of myalgia, however, was higher with placebo (12.1%) than with tafenoquine or mefloquine (both 9.5%) (FDA, 2018c). In the same analysis, the incidence of headache was found to be 30.5% for placebo, 33.3% for tafenoquine, and 46.3% for mefloquine; the incidence of vertigo and tinnitus was 0% for placebo and tafenoquine, and 1.4% for mefloquine; and the incidence of fatigue/lethargy and visual disturbance was similar among the three groups. In an additional study (Leary et al., 2009) that compared tafenoquine with placebo, the incidence of myalgia in the tafenoquine group was higher than in the placebo group (7.4% versus 0%), while headache, fatigue, lethargy, and visual disturbance as well as the category of falls, dizziness, and lightheadedness were ânumerically higherâ for placebo than tafenoquine. The one case of tinnitus reported in the tafenoquine group remained unresolved at study end. Three studies in the safety set had a mefloquine comparator arm, and people with a history of psychiatric disorders were excluded; another study in the set excluded those with a history of drug or alcohol abuse (FDA, 2018c). The FDA briefing document states that there was no systematic monitoring of psychiatric symptoms, such as actively asking participants about symptoms or using a rating scale for psychiatric symptoms, in the trials in the safety set and that âthis may result in an underestimation of the actual incidence of neurologic adverse eventsâ (FDA, 2018c). In the safety set, psychiatric adverse reactions were reported in 3.9% (32/825) of participants receiving tafenoquine, 3.2% (10/309) of the participants receiving mefloquine, and 0.8% (3/396) of the participants receiv- ing placebo. Insomnia was reported in 1.2% (10/825) of the participants in the tafenoquine group, 0.8% (3/396) in the placebo group, and 0.3% (1/309) in the mefloquine group. Psychiatric adverse events led to discontinuation of the drug in two participants taking tafenoquine (one suicide attempt; one case of depression), one taking mefloquine (severe anxiety), and none taking placebo. In a study within the safety set that included deployed Australian soldiers (Nasveld et al., 2010), the incidence of any kind of adverse sleep symptom (insomnia, abnormal dreams, nightmares, sleep disorder, somnambulism) was similar between the tafenoquine (3.5%) and mefloquine groups (3.7%) (FDA, 2018c). Anxiety was reported in 0.8% (4/492) of the tafenoquine group versus no reports in the mefloquine group (0/162); depression was reported in 0.2% (1/492) of the tafenoquine group and 0.6% (1/162) of the mefloquine group; and euphoric mood and agitation were each reported in 0.4% (2/492) of the tafenoquine group compared with no reports in the mefloquine group. Use of the approved prophylactic loading and maintenance dosages of tafenoquine is associated with adverse gastrointestinal events of abdominal pain, diarrhea, nausea, and vomiting (FDA, 2018c). The safety profile of tafenoquine when administered without food was not assessed in the drug-development pro- gram (FDA, 2018c). In a pooled analysis of the safety set, gastrointestinal adverse
TAFENOQUINE 187 reactions with an incidence â¥1% were abdominal pain, upper abdominal pain, constipation, diarrhea, dyspepsia, gastritis, nausea, and vomiting (FDA, 2018c). Diarrhea (12.7%) and vomiting (3.8%) occurred at a higher incidence in the tafenoquine group than in the placebo group (5.8% and 1.5%, respectively) and the mefloquine group (10.7% and 3.6%, respectively) (FDA, 2018c). Two with- drawals due to gastrointestinal effects occurred among tafenoquine recipients (one with upper abdominal pain; one with irritable bowel syndrome) (FDA, 2018c). However, in the study of deployed Australian soldiers (Nasveld et al., 2010), the incidence of gastrointestinal adverse events (â¥1%) was lower in the tafenoquine group than in the mefloquine group: diarrhea, 18.1% versus 19.8%; nausea, 6.9% versus 9.3%; vomiting, 4.9% versus 5.6%; and abdominal pain, 4.9% versus 7.4% (FDA, 2018c). Regarding tafenoquine-associated eye disorders, the FDA briefing document, referring to the study in deployed Australian soldiers, notes that baseline retinal photography was not performed and that the incidence of reported retinal disor- ders was similar in the tafenoquine (1.4% [7/492]) and mefloquine (1.9% [3/162]) groups (FDA, 2018c). In a malaria treatment trial (not part of the safety set) that assessed ophthalmic measures, retinal pigmentation was observed on day 28 in 19.6% (9/46) of tafenoquine recipients and was still present in eight people at day 90, compared with only 4.2% (1/24) of chloroquine/primaquine recipients who had developed retinal findings; no retinal findings were associated with vision changes. In summarizing, the FDA briefing document notes that tafenoquine is associated with reversible vortex keratopathy and that the risk of adverse effects on vision and the retina cannot be adequately ascertained based on the data available. The FDA briefing document notes that there were no serious cardiac events in tafenoquine recipients in the safety set and that no cardiac adverse events occurred at an incidence â¥1% (FDA, 2018c). No information on comparators was provided. Taking FDA-approved loading/maintenance dosages of tafenoquine is associ- ated with a decrease in hemoglobin levels, hemolytic anemia, and methemoglobin- emia (FDA, 2018c). In a pooled analysis of the safety set, 0.4% (3/825) of tafeno- quine recipients withdrew because of decreased hemoglobin, compared with 0.3% (1/396) of the placebo recipients and none (0/309) of the mefloquine recipients. In the safety set, mild, transient glomerular filtration rate decreases led two participants (0.2%) in one study to leave the study (Leary et al., 2009); the individ- ualsâ serum creatinine remained within normal range (FDA, 2018c). In the safety set, five participants (0.6%) in the tafenoquine group and two (0.5%) in the placebo group experienced glomerular filtration rate decreases, compared with none in the mefloquine group; these were classified as serious adverse events. Creatinine changes also occurred in three (0.4%) participants in the tafenoquine group, one (0.3%) in the placebo group, and three (1%) in the mefloquine group. In one study from the safety set (Nasveld et al., 2010), mean serum creatinine increases from baseline in the tafenoquine and mefloquine groups were not clinically significant (FDA, 2018c). In this study, a long-term renal follow-up study was conducted in a
188 LONG-TERM HEALTH EFFECTS OF ANTIMALARIAL DRUGS cohort (tafenoquine, n = 147; mefloquine, n = 36) with serum creatinine concentra- tions â¥0.23 mg/dL greater than baseline at the end of the prophylactic phase or at follow-up (FDA, 2018c). In the published study (Nasveld et al., 2010), the authors noted that at follow-up, 6â8% of participants in both groups had creatinine values that were still 25% above baseline, but few values were outside the normal range, and no values were considered clinically significant. Other Reviews Novitt-Moreno et al. (2017) performed an integrated safety analysis of the same five malaria-prophylaxis trials referred to as the safety set above. The authors stratified the study population by deployment status (Australian National Defence soldiers taking tafenoquine [n = 492] and non-military residents taking tafenoquine [n = 333] or placebo [n = 295]) and reported that several adverse events occurred in both tafenoquine-deployed and tafenoquine-resident groups at a higher incidence than in the placebo resident group: diarrhea, nausea, vomiting, ringworm, gastro- enteritis, nasopharyngitis, sinusitis, tonsillitis, laceration, ligament sprain, back pain, neck pain, and rash. The frequency of adverse events reported by the placebo- resident (64.1%) and tafenoquine-resident (67.6%) groups were generally similar. However, several adverse events, including ear and labyrinth disorders, psychiatric disorders, eye disorders, gastrointestinal disorders, immune system disorders, infec- tions and infestations, musculoskeletal and connective tissue disorders, and skin and subcutaneous tissue disorders were reported at higher rates in the tafenoquine- deployed group than in either of the resident groups, suggesting that deployment contributed to occurrence of some of the adverse events. The adverse events that occurred in the tafenoquine-deployed group with an incidence of at least 10% more than in the tafenoquine-resident group or the placebo-resident group were, respectively, diarrhea (18.1% versus 4.8% versus 3.1%), gastroenteritis (37.2% versus 7.8% versus 5.8%), and nasopharyngitis (19.7% versus 3.3% versus 2.4%) (Novitt-Moreno et al., 2017). When the authors compared psychiatric adverse events in the tafenoquine-deployed group with the tafenoquine-resident group and the placebo-resident group, the number of cases was 25 (5.1%) versus 7 (2.1%) and 3 (1.0%), respectively, for all psychiatric disorders. Only comparisons between the tafenoquine-deployed group and the tafenoquine-resident group were reported for specific psychiatric adverse events; 18 (3.7%) versus 3 (0.9%) for psychiatric disorders affecting sleep; 8 (1.6%) versus 2 (0.6%) for insomnia; 5 (1%) versus 0 for abnormal dreams; and <1% (for both groups) for any other itemized psychiatric disorders. After reviewing medical histories and adjusting for confounding illnesses or events for individuals with insomnia or sleep-related disorders, similar percent- ages (0.3â0.4%) of the two groups experienced insomnia or sleep-related disorders. Eye disorders were reported in 17% of tafenoquine-deployed users versus 10.2% of the tafenoquine-resident users, and 10.5% of the placebo-resident users (Novitt-Moreno et al., 2017). However, ophthalmologic assessments were done
TAFENOQUINE 189 in a cohort of the deployed tafenoquine users (Nasveld et al., 2010), enabling identification of vortex keratopathy, which was reported in 13.8% of the subgroup and accounted for the majority of eye disorders in deployed users. The vortex kera- topathy was determined to be reversible and cause no functional vision changes (Novitt-Moreno et al., 2017). No breakdown of the remaining eye disorders in the tafenoquine-deployed group or of the eye disorders in the tafenoquine-resident group or the placebo group was provided. Post-Cessation Adverse Events A total of 423 abstracts or article titles were identified by the committee for inclusion for tafenoquine. After screening, 116 abstracts and titles remained, and the full text for each was retrieved and reviewed to determine whether it met the committeeâs inclusion criteria, as defined in Chapter 3. The committee reviewed each article and identified seven epidemiologic studies that met its inclusion crite- ria (Ackert et al., 2019; Green et al., 2014; Leary et al., 2009; Miller et al., 2013; Nasveld et al., 2010; Rueangweerayut et al., 2017; Walsh et al., 2004). These studies were reviewed comprehensively and are summarized below. A table that gives a high-level comparison (study design, population, exposure groups, and outcomes examined by body system) of each of the seven epidemiologic stud- ies that examined the use of tafenoquine and that met the committeeâs inclusion criteria is presented in Appendix C. Five studies (Ackert et al., 2019; Green et al., 2014; Miller et al., 2013; Rueangweerayut et al., 2017; Walsh et al., 2004) used off-label dosages of tafenoquine. Military and Veterans Nasveld et al. (2010) conducted a randomized double-blind controlled study to compare the safety and tolerability of tafenoquine for 26 weeks followed by placebo for 2 weeks (n = 492) or mefloquine for 26 weeks followed by prima- quine for 2 weeks (n = 162) for malaria prophylaxis in male and female Austra- lian soldiers aged 18â55 years. The soldiers were deployed on United Nations peacekeeping duties to East Timor. They were predominantly young, Caucasian men and were judged to be healthy by a medical history and physical examina- tion with normal hematologic and biochemical values and to be G6PD normal. Participants with a history of psychiatric disorders or seizures were excluded, as were women who were pregnant, lactating, or unwilling or unable to comply with contraception. A subset of 98 participants (77 from the tafenoquine group and 21 from the mefloquine group) underwent extra safety assessments at baseline and at the end of the prophylactic phase to investigate drug-induced phospholipidosis and methemoglobinemia as well as ophthalmic and cardiac safety. Safety and toler- ability assessments occurred at weeks 2 and 12 during the follow-up phase after the last dose of study medication, and there was additional telephone follow-up
190 LONG-TERM HEALTH EFFECTS OF ANTIMALARIAL DRUGS at weeks 18 and 24. Adverse-event monitoring was supplemented by a review of the subjectsâ medical records. In the safety subgroup, vortex keratopathy (corneal deposits) was found in 69 of 74 (93.2%) tafenoquine recipients and 0 of 21 meflo- quine recipients. The changes were not associated with visual disturbances; 10% persisted at 6 months, but complete resolution occurred in all by 1 year. Mean methoglobin levels increased by 1.8% in the tafenoquine group (compared with 0.1% in the mefloquine group), but the increase resolved by week 12 of follow- up. A small reduction in mean QT interval was also seen in tafenoquine recipients (compared with a small increase in QT interval in the mefloquine group); whether the change in interval resolved with time is not stated, but none of these findings were considered to be clinically significant by the authors. The authors stated that during the relapse follow-up phase, 203 (41.3%) tafenoquine/placebo subjects and 53 (33.9%) mefloquine/primaquine subjects reported adverse events, but no notable difference between the groups in the incidence or nature of events was observed. The adverse events are not named nor is their timing specified. Authors do state that at follow-up, 6â8% of participants in both arms had creatinine values that were 25% above the baseline, but few had values outside the normal range, and none were considered clinically significant. The overall study design was rigorous, with randomization to medications, tem- poral ordering of exposures and outcomes, systematic data collection, high adher- ence to assigned medications, and little attrition from the study (94% of subjects in both arms completed the trial), and the study was conducted in a highly relevant population for the committeeâs task. However, it is limited in the information it pro- vides with respect to persistent adverse events for tafenoquine because of the small number of subjects (n = 77) who underwent detailed safety evaluation as well as the use of mefloquine as a comparison exposure rather than a placebo or no antimalarial exposure. Exposure assessment was fairly strong, owing to consistent measurements across the arms of the study and the use of medication logs to measure adherence prospectively. However, all exposure was self-reported, with no direct observation or biologic measures. Most adverse events were not assessed in a systematic way, limiting the quality of these measures. In addition, with the exception of few mea- sures (ophthalmic, cardiac, and methoglobin levels) in the safety evaluation subset, the timing of adverse events was not clearly specified beyond the prophylaxis phase, and therefore the persistence of adverse events could not be ascertained. While the statistical power was sufficient for the primary goal of the study, which was to assess the antimalarial efficacy, the sample size was insufficient for the study of most per- sistent or latent adverse events. The study reported persistent vortex keratopathy that resolved by 1 year and had no effect on vision. There were no persistent increases in methemoglobin or cardiac outcomes. Walsh et al. (2004) conducted a randomized double-blind placebo-controlled study in 205 healthy Thai soldiers aged 18â55 years (median 23 years). The primary objective was to assess tafenoquineâs efficacy as malaria prophylaxis; secondary outcomes were safety and tolerability. Laboratory tests were conducted
TAFENOQUINE 191 monthly during drug administration and then for up to 2 months after the last medication dose. Participants were screened for G6PD deficiency and had not received antiÂ alarial treatment within the prior 2 weeks (5 weeks for mefloquine). m Volunteers were examined for malaria and received a 7-day course of artesunate and Â oxycycline, administered concurrently, to eliminate subpatent4 blood stages d of malaria if needed. In any case of patent parasitemia, parasite clearance was con- firmed at the end of presumptive therapy. After the presumptive therapy, soldiers received a loading dose of tafenoquine 400 mg (base) daily for 3 days, followed by 400 mg monthly (n = 104) or placebo (n = 101) for up to 5 consecutive months. The tafenoquine dosage is not within FDA-approved labeling for prophylaxis. Monthly doses were administered under direct observation, within a window of 25â31 days after a previous dose, and within 2 hours of a meal or light snack, for better gastroÂntestinal tolerance and bioavailability. Volunteers who developed i parasitemia while receiving the medication and who were classified as having had treatment failure received the presumptive therapy regimen and were given the option of no further prophylaxis, doxycycline at 100 mg daily, or open-label tafenoquine administered at a loading dose of 400 mg for 3 days and then 400 mg weekly. Adverse events were recorded daily during the 3-day loading dose and then at approximately 24 hours after each dose, according to a predefined coded checklist of the most commonly expected adverse events. Serious adverse events were defined as those requiring hospital admission. All volunteers who had received at least one dose of tafenoquine or placebo medication were included in the safety and tolerability analysis. The follow-up time was measured from the first dose of tafenoquine (day 0) until the date of drug failure, withdrawal from the study (non-malaria-related), loss to follow-up, or study completion (6 months for most volunteers). A total of 17 participants (8.3%) were lost to follow-up; in the pla- cebo group, 5 were reassigned to distant posts and 4 left the service, while in the tafenoquine group, 6 were reassigned and 2 left the service. Methemoglobin levels were monitored in a manner that did not affect blinding. Monthly hematologic and biochemical laboratory values were recorded. Complete blood counts and hepatic and renal function tests were conducted monthly and for up to 2 months after the last drug dose. Group treatment means (95%CIs) were computed and compared by use of Studentâs t test (unpaired and paired if appropriate). No differences were reported between the treatment arms for hepatic and renal function outcomes, and the authors note, âFor [complete blood counts], there were no significant differences between the mean monthly values of the tafenoquine and placebo recipients for any parameter throughout the study or any significant changes from baseline values in either group.â Adverse events were summarized by the two treatment arms, but the study was not designed to reliably estimate adverse event rates with a low incidence or powered to detect differences in those events between the two groups. 4â Infections in persons who tested negative for PlasmodiumÂ parasitemia by rapid malaria diagnostic testÂ but tested positive by polymerase chain reaction (Kobayashi et al., 2019).
192 LONG-TERM HEALTH EFFECTS OF ANTIMALARIAL DRUGS The overall study design was rigorous, with randomization, double Â linding, b and a placebo control. There was also temporal ordering of exposures and outcomes, systematic data collection, medication-adherence monitoring, and relatively little attrition from the study. The population of Thai soldiers is also rel- evant for the population of interest, and there were few exclusion criteria beyond prior antimalarial treatment and age >55 years; participants had only to be âin good general healthâ and have normal G6PD screens. Exposure assessment was strong, with direct observation of dosing. In terms of persistent or latent events, a major limitation is that, with the exception of complete blood counts and hepatic and renal function tests conducted monthly, data collection was not systematic. In addition, the study was powered for the primary outcome (an 85% reduction in the 6-month cumulative incidence of slide-proven malaria), which resulted in approximately 90 subjects per arm; as the authors acknowledge, this provides insufficient power to detect differences in rare adverse safety between the two treatment arms. All serious adverse events reported were during the prophylaxis period. It is unknown whether no serious adverse events occurred after that time or the post-drug-cessation data were not collected or reported. In summary, the study reported persistent adverse hematologic, hepatic, and renal outcomes, but the study was insufficient to examine a broad set of persistent or latent adverse events. Research Volunteers Ackert et al. (2019) conducted a randomized single-blind controlled trial to compare the ophthalmic safety of a single dose of tafenoquine (300 mg) (n = 306) with that of placebo (n = 161) in adults at three U.S. study centers. The tafenoquine dose is not within FDA-approved labeling for prophylaxis. Partici- pants were men and women aged 18â45 years, weighing 35â100 kg, and deemed healthy by an investigator, with normal hematology and chemistry values. Exclu- sion criteria included current or chronic history of liver disease, known hepatic or biliary abnormalities, hemoglobin values outside the lower limit of normal range, G6PD deficiency, and a QTcF interval of >450 ms. Participants with reproductive potential had to be capable of adherence to contraception. Pregnant and lactat- ing females were excluded. Key ophthalmic exclusion criteria were a bilateral best-corrected visual acuity of â¤72 letters; eye disease that could compromise ophthalmic assessments; an intraocular surgery or laser photocoagulation within 3 months of dosing; high myopia (equal to or worse than â6.00 diopters); anterior, intermediate, or posterior uveitis or history of significant intraocular infectious disease or another active inflammatory disease; spectral domain optical coherence tomography (SD-OCT) central subfield thickness <250 Î¼m or >290 Î¼m; presence of significant abnormal patterns on fundus autofluorescence (FAF) or ocular abnor- malities on fundus photography at screening; or uncontrolled intraocular pressure >22 mmHg. Outcomes were compared among tafenoquine group members and placebo group members, with an adverse event assessment performed over the
TAFENOQUINE 193 telephone at approximately 30 and 60 days post-cessation and with full ophthalmic exams, including visual field examination, slit-lamp evaluation of anterior segment structures, and SD-OCT and FAF, carried out at baseline and on approximately day 90. One participant in each group met the composite endpoint for retinal changes identified with SD-OCT or FAF. Both subjects had unilateral focal ellipsoid zone disruption at day 90, although it was determined that the tafenoquine-treated subject actually had this anomaly at baseline and was enrolled in error. There were no subjects with bilateral retinal changes. Additional secondary endpoints for ophthalmic safety were also examined; there were no treatment differences in central subfield thickness, central retinal/lesion thickness, macular cube volume, subretinal fluid thickness, or best-corrected visual acuity. There were no clinically important changes from baseline to day 90 in intraocular pressure. One subject in the tafenoquine group was reported to have vortex keratopathy; however, it was later determined to be a Lasik scar with calcium deposits. General safety events were also collected, in particular, the frequency of adverse events and serious adverse events. The frequency of adverse events was similar between groups, and no serious or severe adverse events were reported during the study, although the timing of the adverse events was not clear. The study design was strong, with randomization and a blinding of the outcome assessment, sufficient power for the study questions, high follow-up rates (93% in the tafenoquine group and 96% in the placebo group), treatment administration directly observed, and systematic measurement of ophthalmic outcomes.Â Systematic measurement of ophthalmic endpoints was performed. Green et al. (2014) conducted a Phase I single-blind randomized placebo- and active-controlled parallel-group study at two U.S. sites to investigate whether tafenoquine at supratherapeutic and therapeutic concentrations prolonged cardiac repolarization in healthy volunteers aged 18â65 years. The primary objective was to demonstrate a lack of effect of supratherapeutic tafenoquine (1,200 mg) on QTcF as determined by the baseline-adjusted maximum time-matched QTcF effect as compared with placebo (ÎÎQTcF). Secondary objectives included demonstrat- ing a lack of effect of tafenoquine therapeutic doses (300 and 600 mg) on ÎÎQTcF, describing tafenoquine pharmacokinetics, and characterizing the pharmacoÂ inetic/ k pharmacodynamic relationship between tafenoquine concentrations and any change in QTcF. The tafenoquine doses are not within the FDA-approved label- ing for prophylaxis. Participants (n = 52 per arm) returned for follow-up at 5, 10, 24, and 60 days after the last dose of study medication. Safety was evaluated by physical examination, vital signs, clinical laboratory tests (hematology, biochem- istry, and urinalysis) and adverse event monitoring. While mild, dose-related elevations in methemoglobin levels occurred, levels returned to normal by the final follow-up visit, and there were no signs or symptoms of methemoglobinemia. Resting single 12-lead electrocardiograms (ECGs) were performed at screening and at days â2, 1, 2, 3, 4, 5, 6, 27, and 63. No clinically significant abnormalities were reported from the ECGs. The strengths of the study include a randomized
194 LONG-TERM HEALTH EFFECTS OF ANTIMALARIAL DRUGS design, multiple tafenoquine-dose arms, and a placebo control arm. The study also included a Â oxifloxacin (positive [active] control) arm, but moxifloxacin is not m FDA approved for malaria prophylaxis, and those results are not reported here. The temporality of exposure before the outcomes was guaranteed by the design, and there was low attrition from the study arms. While the study was sufficiently powered for the main comparisons of interest, a design limitation for the commit- teeâs purposes is that each study arm had only 52 participants, limiting the power to detect persistent adverse events. Drug exposure was conducted in a supervised clinical laboratory setting and thus is very strong. Outcome assessment for the outcomes of interest was systematic, and cardiac-related safety was evaluated in standardized ways, including a physical examination (including ECGs), vital signs, clinical laboratory tests, and adverse event monitoring 24 and 60 days after the final drug exposure. However, a broader set of potential adverse events was not collected in a systematic way, and the results presented did not differentiate their timing. The study reported no persistent adverse methemoglobin or cardiac outcomes, but the study was insufficient to examine a broad set of persistent or latent adverse events. Leary et al. (2009) conducted a randomized double-blind study to assess the ophthalmic and renal effects of tafenoquine 200 mg weekly versus placebo for 24 weeks in 120 healthy men and women between the ages of 15 and 55 years (mean age 33.9 years) recruited from the United States and the United Kingdom. Exclu- sion criteria included a history of eye surgery, corneal or retinal abnormalities, current use of eye drops, participation in activities that could affect vision (e.g., scuba diving, exposure to high altitude, or excessive sunlight), a history of drug or alcohol abuse, and the use of prescription medications within 30 days of the studyâs start. The 120 participants were randomized in a 2:1 ratio: 81 were assigned to tafenoquine 200 mg once daily for 3 consecutive days (600 mg loading dose), fol- lowed by 200 mg once weekly for 23 weeks (24 weeks of drug administration); 39 were assigned to placebo. In addition to regular screening during the prophylactic phase, participants were followed for 24 weeks, with data collected at weeks 12 and 24 after drug cessation. The primary ophthalmic endpoint was the proportion of persons with impaired night vision as measured by the forward light scatter test, a test that is sensitive to the presence of scatter secondary to corneal depos- its. Secondary ophthalmic endpoints included further assessment of night vision, assessment of macular function, visual acuity, color vision, corneal deposits, and changes in retinal morphology. For ophthalmic measures, there were no meaning- ful differences between the study groups in changes to high-contrast visual acu- ity and measured color vision; the majority of people (>98% in the tafenoquine group, >96% in the placebo group) had normal test results throughout the study. At screening, corneal deposits were reported in 10 of 70 (14.3%) and 7 of 32 (21.9%) in the tafenoquine and placebo groups, respectively. Treatment-emergent corneal deposits occurred in 15 of 60 (25%) of the tafenoquine group and 4 of 25 (16%) of the placebo group, with no observed pattern for time to onset. In 14 tafenoquine-
TAFENOQUINE 195 dosed participants, new-onset corneal deposits resolved within 12 weeks of onset, in most cases during active use; in the one remaining person, the deposits resolved by 24 weeks after drug cessation. Another tafenoquine recipient showed retinal abnormalities during the follow-up period, but this was not associated with a decrement in visual acuity, foveal sensitivity, or visual field up to 11 months after drug cessation. The primary renal endpoint was tafenoquineâs effect on the mean change in the glomerular filtration rate (GFR) compared with placebo. Secondary renal endpoints included the number of participants with significant changes in GFR, serum creatinine, or urinalysis findings at any time after drug administra- tion. Of those with urinalysis results at week 24, clinically important findings were found in 3.6% and 11.5% of participants in the tafenoquine and placebo groups, respectively. Two tafenoquine recipients showed hematuria greater than trace. None of these cases were associated with a significant change in glomerular filtra- tion rate or serum creatinine concentration; all resolved without treatment. One tafenoquine recipient displayed hemolytic anemia at week 3, with a 17% decrease in hemoglobin and a 23% decrease in haptoglobin. After ceasing tafenoquine therapy, hematology values returned to normal within 12 weeks. Another tafeno- quine recipient showed creatinine phosphokinase values outside the normal range during the follow-up period; further information was not provided. Strengths of this study include a randomized design and a placebo control group. The temporality of the exposure before outcomes was ensured by the design. A weakness is that attrition was relatively high, with only 58 of 81 (71.6%) tafenoquine recipients and 29 of 39 (74.3%) placebo recipients completing the 24-week visit post-drug-cessation. A design limitation for the committeeâs pur- poses is that, while powered for the primary outcome of interest, the number of participants (79 in the tafenoquine arm; 39 in the placebo arm) provided limited power for detecting persistent adverse events (and insufficient power for even the secondary endpoints). Exposure assessment was considered to be strong, with the drug administration supervised directly in some weeks and confirmed by telephone in others. The outcome assessment for the primary and secondary outcomes of interest (ophthalmic and renal) was systematic; ophthalmic tests and hematologic and biochemical measures were obtained at 12 and 24 weeks post-drug-cessation. Most outcomes examined showed no abnormal results at any time point, and in nearly all individuals the concurrent ophthalmic or renal problems resolved by 24 weeks post-dosing. However, a broader set of potential adverse events was not collected in a systematic way, and the reported data did not distinguish their timing, so the information was insufficient for examining a broad set of persistent or latent adverse events. Miller et al. (2013) conducted a small randomized double-blind three-arm study to examine the effect of tafenoquine in healthy men and women in the United States aged 18â55 years. This was designed as a safety trial for malaria treatment, but since one arm was tafenoquine alone, the healthy participants did not have malaria, and the follow-up was 56 days, the committee believed it
196 LONG-TERM HEALTH EFFECTS OF ANTIMALARIAL DRUGS might be informative. The tafenoquine 450 mg dose is not within FDA-approved labeling for prophylaxis. Participants were administered 600 mg chloroquine on days 1 and 2 (n = 20); or 450 mg tafenoquine on days 2 and 3 (n = 20); or 600 mg chloroquine on day 1, 600 mg chloroquine plus 450 mg tafenoquine on day 2, and 300 mg chloroquine plus 450 mg tafenoquine on day 3 (n = 20). The exclusion criteria included cardiac conduction abnormalities on 12-lead ECGs; a history of cardiovascular disease or clinically significant arrhythmia; aspartate aminotransferase, alanine aminotransferase, or alkaline phosphatase >1.5 times the upper limit of normal or total bilirubin outside the normal range at screening; documented G6PD deficiency as determined by a quantitative enzyme activity assay; a history of hemoglobinopathy or methemoglobinemia or a methemo- globin percentage above the reference range at screening; or a history of retinal eye surgery, Lasik surgery within 90 days, or retinal or corneal abnormalities. Participants were also excluded if they had taken prescription or non-prescription drugs in the previous 7 (or 14, for enzyme inducers) days. While adverse events were reported only through day 7, clinical laboratory tests and methemoglobin and ophthalmic assessments were performed at screening or at day â1, multiple times throughout the study, and then again at day 56. As the committeeâs focus is tafenoquine used for malaria prophylaxis, the findings for the tafenoquine- alone arm are emphasized here. Changes in vital signs and clinical laboratory values were similar across treatment groups and were reported to be clinically insignificant. A trend for mild declines (1.5â2.5 g dlâ1) in hemoglobin was noted in a greater proportion of tafenoquine-treated subjects than in those treated with chloroquine alone (tafenoquine 22%, tafenoquine/chloroquine 17%, and chloro- quine 4%). Two African American females who received tafenoquine experienced a decrease in hemoglobin >2.5 g dlâ1 (2.8 and 3.0 g dlâ1) on day 10, but those values returned to baseline by day 56. No clinically significant changes from baseline were found in macular function across treatment groups. A trend of minor declines of visual acuity was seen in the tafenoquine-treated group; how- ever, the study was not powered to compare differences between treatments. One tafenoquine recipient showed a clinically significant reduction from baseline in visual acuity at day 28 that spontaneously resolved by day 56 (logMAR scores of â0.1, 0.3, and 0, at baseline, day 28, and day 56, respectively). The subject had no retinal abnormalities, eye-related adverse events, or vortex keratopathy. Mean percentage methemoglobin measures increased slightly from baseline in the groups that received a regimen containing tafenoquine. Maximal mean changes from baseline were observed on day 14 (<1% chloroquine, 4% tafenoquine, and 6% chloroquine/tafenoquine), and elevations in three women in the tafenoquine/ chloroquine group were greater than 10%, but mean methemoglobin values for the three women returned to baseline by day 28 and for all others by day 56. The overall study design was strong, as it was randomized and had double blinding. There was also a clear temporal ordering of exposures and outcomes, direct observation of medication adherence, and relatively low attrition. A design
TAFENOQUINE 197 limitation for the committeeâs purposes is that, while sufficiently powered for the primary pharmacokinetic outcome of interest, the number of participants was very small (58 across three treatment arms) and thus provided limited power for detecting potentially rare persistent or latent adverse events. Clinical laboratory values and vital signs, methemoglobin levels, and ophthalmic measures were evaluated 1 and 2 months post-drug-cessation. Beyond these few specific assess- ments, the evaluation of general persistent adverse events was limited, with a collection of adverse events and serious adverse events performed only during the 7-day confinement period. In summary, the very small size of this study and the lack of assessment of a broad set of adverse outcomes makes the study minimally informative for this review. Rueangweerayut et al. (2017) used a prospective observational study design to examine the tolerability of tafenoquine (100, 200, or 300 mg, single-dose) compared with primaquine (15 mg for 14 days) in a total of 51 healthy Thai females who were heterozygous for Mahidol-variant G6PD deficiency (40â60% of adjusted site defined median value for G6PD-normal males) (n = 6 for each tafenoquine dosage arm; n = 5 for primaquine) or G6PD normal (â¥90% of adjusted site median normal value) (n = 6 for each tafenoquine dosage arm; n = 6 for primaquine). Two additional cohorts of G6PD-deficient participants with greater G6PD activity (61â80% and >80% of site median normal value; n = 2 and n = 5, respectively) were administered 200 mg of tafenoquine. The 300 mg tafenoquine dose is not within FDA-approved labeling for prophylaxis. The pri- mary outcome was the maximum absolute decrease in hemoglobin or hematocrit from pre-treatment up to day 14 following treatment. The subsequent outpatient follow-up visits were at days 21, 28, and 56. The safety assessments included adverse event monitoring, vital signs, 12-lead ECGs, clinical biochemistry, hematology (including methemoglobin determined by oximetry), and urinaly- sis.Â The tafenoquine dose escalation was halted when hemoglobin decreased by â¥2.5 g/dL or the hematocrit declined â¥7.5% versus pretreatment values. In the G6PD-deficient arms, dose-limiting effects were reported to occur in 3 of 3 of the 300 mg dose tafenoquine arm and 3 of 5 of the primaquine arm; of these, two recipients of each drug experienced both a decrease â¥2.5 g/dL in hemoglobin and a decrease â¥7.5% in hematocrit versus pre-treatment, with the greatest decrease in hemoglobin with tafenoquine being â2.95 g/dL. No tafenoquine recipient showed methemoglobin levels >5.0%. Among the primaquine recipients, 4 of 6 of the G6PD-normal group showed sustained elevations in methemoglobin (maximum values 5.5â13.1%); in the G6PD-deficient group, values did not exceed 3.9%. The authors reported that there were no accompanying clinical symptoms associated with hemolysis or increased methemoglobin levels, no other clinically important changes in laboratory measures, and no notable ECG changes.Â The study was limited by the very small sample size and the narrow range of enzyme activities examined, making it minimally informative for this review.
198 LONG-TERM HEALTH EFFECTS OF ANTIMALARIAL DRUGS OTHER IDENTIFIED STUDIES OF TAFENOQUINE IN HUMAN POPULATIONS The committee reviewed five additional studies on malaria prophylaxis involving tafenoquine, but they were excluded because they did not distinguish between adverse events that occurred â¥28 days post-cessation of tafenoquine and adverse events that occurred during tafenoquine use or shortly after cessation (Brueckner et al., 1998; Hale et al., 2003; Lell et al., 2000; Nasveld et al., 2002; Shanks et al., 2001). In addition to those epidemiologic studies that did not meet criteria for inclusion, the committee also reviewed case reports, studies of tafeno- quine used for the treatment of malaria, and studies of tafenoquine that considered demographic differences. In its approval letter, FDA stated that it had determined that an analysis of the spontaneous postmarketing adverse events reported would not be sufficient to assess a signal of serious risks of ophthalmic, psychiatric, and hematologic adverse reactions, nor would the pharmacovigilance system that FDA is required to establish (FDA, 2018b). Therefore, FDA has required the manufacturer to conduct two studies. One will be an observational study to evaluate safety, including neu- rologic, hypersensitivity, psychiatric, and hematologic adverse reactions, in people taking tafenoquine for the prophylaxis of malaria. The study, which will compare tafenoquine with atovaquone/proguanil in travelers (>10,000 participants), is in the planning stages.5 The second required study, which is currently recruiting participants (NCT #03320174), is a randomized double-blind placebo-controlled study that will enroll 600 healthy G6PD-normal volunteers. Participants who meet the eligibility criteria will be randomized (ratio 1:1) to receive a loading dose of tafenoquineÂ 200 mg (2 Ã 100 mg tablets) or placebo daily for 3 days, followed by the study treatment (tafenoquineÂ 200 mg or placebo) once weekly for 51 weeks, with safety follow-up visits at weeks 4, 12, 24, and 52. Participants will return to the clinic at week 64 for an end-of-study visit. A participant who has an ongo- ing adverse event at the week 64 visit will be assessed up to three more times at approximately 12-week intervals or until resolution or stabilization of the adverse event, whichever is earlier. Treatment Studies and Case Report While the use of antimalarial drugs for the treatment of malaria falls outside the scope of the committeeâs task, because tafenoquine is so new to the market the committee wanted to ensure that it captured any adverse event from such studies that might raise concern. A Cochrane review published in 2015 included a meta- analysis of three randomized controlled treatment trials that compared tafenoquine 5â Personal communication to the committee, Geoffrey Dow, M.B.A., Ph.D., Chairman and Chief Executive Officer, 60 Degrees Pharmaceuticals, LLC, on January 28, 2019.
TAFENOQUINE 199 plus chloroquine to chloroquine alone in some arms and to primaquine plus chlo- roquine in other arms in persons with P. vivax (Rajapaske et al., 2015). Persons with G6PD deficiency were excluded, and all participants received chloroquine therapy. The participants in these trials took higher doses of tafenoquine, 300â600 mg per day for up to 3 days versus the approved prophylactic dosage of 200 mg daily for 3 days followed by 200 mg weekly. In the comparison of tafenoquine plus chloroquine to chloroquine alone, there was no difference in serious adverse events (three trials, 358 participants) and no difference for any reported adverse events (one trial, 272 participants). There was a dose-dependent rise in methemoglobin in tafenoquine-treated groups that was asymptomatic. There was also no difference in serious or total adverse events in tafenoquine versus primaquine groups (two trials, 323 participants). Three additional treatment trials published after the Cochrane review and one case report are summarized below. Fukuda et al. (2017) studied men and women 20â60 years of age with malaria and no prior ophthalmic conditions who received 400 mg of tafenoquine daily for 3 days (n = 46) compared with those who received chloroquine followed by primaquine for 14 days (n = 24). Participants were followed up to day 120. The adverse events that occurred in tafenoquine recipients more frequently than in chloroquine/primaquine recipients were methemoglobinemia (defined as metho- globin level >8.5%) (47.8% versus 0); vortex keratopathy (31.8% versus 0); upper respiratory tract infection (30.4% versus 20.8%); headache (30.4% versus 16.7%); dizziness (26.1% versus 12.6%); retinopathy/retinal disorder (22.7% versus 4.2%); thrombocytopenia (13% versus 0); nausea (13% versus 12.5%); aesthenia (8.7% versus 8.3%); and dyspepsia, diarrhea, hepatomegaly, hypokalemia, and myalgia (6.5% each versus 4.2%, 0, 0, 4.2%, 4.2%, respectively). There were no clinically relevant changes in visual acuity or the results of macular function tests and no evidence of clinically relevant ocular toxicity, although early retinal morphologic changes could not be ruled out in one case. Lacerda et al. (2019) enrolled 522 men and women â¥16 years of age, all of whom received a 3-day course of chloroquine (total dose of 1,500 mg) to treat malaria. In addition, participants were assigned to receive a single 300 mg dose of tafenoquine on day 1 or day 2 (n = 260), or placebo (n = 133), or primaquine for 14 days (n = 129). Participants were followed up for 180 days. Adverse events occurring at any point during the 6-month study in tafenoquine recipients with a greater frequency than placebo were dizziness (8.5% versus 3%), vomiting (5.8% versus 5.3%), diarrhea (3.8% versus 3.0%), and a decline in hemoglobin (5.4% versus 1.5%). No adverse event led to withdrawal from the trial. In Llanos-Cuentas (2019), 251 male and female participants with malaria aged 16 years and older received a 3-day course of chloroquine. In addition, partici- pants received a single 300 mg dose of tafenoquine on day 1 or day 2 (n = 166) or Â rimaquine for 14 days starting on day 1 or day 2 (n = 85). The follow-up period p was 180 days. The frequency of adverse events occurring throughout the study period (days 1â180) that were more common in tafenoquine than in primaquine
200 LONG-TERM HEALTH EFFECTS OF ANTIMALARIAL DRUGS recipients included dizziness (16.3% versus 15.3%), vomiting (6.6% versus 5.9%), upper abdominal pain (4.8% versus 1.2%), diarrhea (3.6% versus 3.5%), hemoglo- bin decline (2.4% versus 1.2%), insomnia (1.2% versus 0), urinary tract infection (3.6% versus 3.5%), nasopharyngitis (3.6% versus 2.4%), and fever (1.8% versus 1.2%). All adverse events resolved spontaneously; none led to discontinuation of treatment. A case study (Cannon et al., 2015) reported a 38-year-old man who had been referred to a physician following two incidents of severe rhinitis, wheezing, and breathlessness after airborne exposure to powdered tafenoquine in a tablet-man- ufacturing plant. Exposure to a control dust (lactose) for 15 minutes provoked no symptoms and no changes in forced expiratory volume in one second. Exposure for the same duration to 1% tafenoquine in 250 mg of lactose provoked a 19% fall in forced expiratory volume in one second 10 minutes after challenge and a maximum fall of 32% at 8 hours. Changes in lung function were accompanied by severe rhinitis, which persisted for several days. Selected Subpopulations To date there have been no studies of tafenoquine prophylaxis that have focused on people with comorbid conditions. Pregnant women have been excluded from clinical trials of tafenoquine because of concerns about the potential for G6PD deficiency in the fetus. Sex Differences A difference between women and men in the incidence of gastrointestinal adverse events has been reported. An open-label randomized study in Australian Defence Force members was designed to compare tafenoquine with primaquine as a post-deployment malaria prophylaxis regimen (Nasveld et al., 2002). When a higher-than-anticipated number of early participants taking tafenoquine (400 mg daily for 3 days) experienced nausea and vomiting, the authors theorized that the âroutine doxycycline prophylaxisâ participants were also taking might have increased the likelihood of gastrointestinal effects, so an additional cohort of par- ticipants was added, which was discussed in a separate paper (Edstein et al., 2007). This cohort ceased taking doxycycline 1 day before receiving tafenoquine, either in a single daily dose (400 mg for 3 days) or in a split dose (200 mg twice daily for 3 days) (Edstein et al., 2007). This dose is not within FDA-approved labeling. The frequency of nausea and abdominal distress in women was more than double that in men in both the once-daily group (76 men, 11 women) and the split-dose group (73 men, 13 women). Reports of gastrointestinal disturbances (e.g., nausea, vomiting, diarrhea, abdominal distress) differed significantly between males and females in the once-daily group but not in the split-dose group. In volunteers who experienced gastrointestinal disturbances, the mean plasma tafenoquine concentra-
TAFENOQUINE 201 tions 12 hours after the last dose were approximately 1.3-fold higher in women than in men (meanÂ±SD: 737Â±118 ng/mL versus 581Â±113 ng/mL, respectively). The average body weight of the women was lower than that of the men (66.5 kg versus 81.6 kg, respectively; p < 0.001). Statistical analyses indicated that women weighing less than 78 kg in the once-daily group and 64 kg in the split-dose group were likely to experience gastrointestinal effects. The authors noted the small numbers of women in the study but hypothesized that the increased chance of gastrointestinal effects among those of lower weight was related to the higher drug concentrations achieved in these women. BIOLOGIC PLAUSIBILITY Studies of the use of tafenoquine in supratherapeutic doses conducted in rats (single-dose) and rhesus monkeys found no signs of neurologic toxicity. In a single- dose study in adult rats, doses up to the minimum lethal dose (500 mg/kg) did not result in any evidence of brainstem neuropathology 7 days after administration (the longest time point tested) (60 Degrees Pharmaceuticals, 2018; Dow et al., 2017). In rhesus monkeys, doses at least 27-fold higher than those determined to be clini- cally relevant for radical cure were not associated with clinical neurologic signs or neurodegeneration (60 Degrees Pharmaceuticals, 2018). Berman et al. (2018) reviewed rhesus monkey literature and reported that tafenoquine (unlike the older 8-aminoquinolines pentaquine, pamaquine, and plasmocid) does not cause neuroÂ pathologic changes in the brainstem. Overall, on the basis of these studies, the committee believes that the probability for neurotoxic actions of tafenoquine is low. No data associated with either concurrent or persistent adverse events are reported linking tafenoquine to known mechanisms associated with neuropathology. The committee did not find evidence of biologic plausibility for eye disorders in animal models. No tafenoquine-related ophthalmic pathologies are reported in dogs (Levine et al., 1997a,b). A 6-month toxicity study in rats showed no t Âreatment-related ophthalmic lesions at week 13 or week 26 (Levine, 1996). Like primaquine and other 8-aminoquinolines, tafenoquine causes hemo- lytic toxicity (Baird, 2019). A study in dogs of five different 8-aminoquinoline compounds, including tafenoquine, corroborates reversible methemoglobinemia following administration (Anders et al., 1988). When the methemoglobin-forming properties of tafenoquine were studied in vitro, tafenoquine was found to cause methemoglobin formation at a rate of 140 Â± 2 pmol/min, which is a greater rate than that observed with primaquine. In mice, tafenoquine blunts platelet response to calcium ions, and it increases measures of platelet aggregation, especially with concurrent thrombin exposure (Cao et al., 2017). However, the authors con- cluded that their results âdo not allow any safe conclusions as to the mechanisms underlying the effect of tafenoquine on platelet apoptosis.â In vivo studies would be required to test whether tafenoquine can alter subtle measures of coagulation
202 LONG-TERM HEALTH EFFECTS OF ANTIMALARIAL DRUGS in miceâand potentially in humans. In a study in rats, supertherapeutic doses (400â700 mg/kg) had negative impact on red blood cell parameters and increased liver enzymes (Dow et al., 2017). Again, as is the case with other 8-aminoquinolines, tafenoquine-induced hemolysis and toxicity are enhanced in individuals with G6PD deficiency (Melariri et al., 2015). In an in vitro study (Bhuyan et al., 2016), human erythrocytes from healthy volunteers were exposed to tafenoquine at a clinically relevant dose for 48 hours. Results showed that tafenoquine triggers suicidal erythrocyte death or eryptosis. In a study of tafenoquine in G6PD-normal women and women with heterozygous G6PD deficiency, a single dose of tafenoquine (100â300 mg) in the G6PD-deficient women decreased hemoglobin and hematocrit measures, although not to dangerous levels; the highest dose of tafenoquine lowered hemoglobin to around â3.0 g/dL (â2.65 to â2.95 g/dL in three participants) (Rueangweerayut et al., 2017). The hemolytic potential was dose dependent, and hemolysis was greater in G6PD-heterozygous females with lower G6PD-enzyme activity levels. Tafenoquine tested negative in cell-based assays for point mutations and chro- mosomal aberrations (Levine, 1998). The developmental toxicity of tafenoquine was studied in female rats (maternal and fetal no-observable-effect level was 3 and 30 mg/kg/day, respectively) and rabbits (maternal and fetal no-observable- effect level was 7 and 25 mg/kg/day, respectively) by dosing during gestation days (Levine, 1998). The observed outcomes in rats included a decrease in body weight and food consumption, and enlarged spleen; the observed outcomes in rab- bits included a decrease in body weight and food consumption, decrease in viable fetuses, premature delivery, and abortion. The reproductive toxicity of tafenoquine was investigated by the administration of daily doses of the drug to male rats for 67 days and to pregnant female rats for 23â47 days, which included 29 days of dosing prior to cohabitation in males and 15 days of dosing prior to cohabita- tion in females (Levine, 1998). The 15 mg/kg daily dose of tafenoquine affected oocyte maturation but not ovulation, mating behavior, implantation, or embryonic development. The no-observable-effect level for reproductive capability in males and females was 15 and 5 mg/kg/day, respectively. There was no evidence that toxicokinetic data were generated in any of these studies. The authors also did not discuss putative mechanisms for the observed toxicities. Manifestations of tafeno- quine neurotoxicity seemed to be rare in these studies. The extensive preclinical toxicity data described in these reports do not provide many mechanistic clues to help explain potential persistent or latent adverse effects of tafenoquine in humans. SYNTHESIS AND CONCLUSIONS Tafenoquine was approved by FDA in 2018 for malaria prophylaxis. Seven epidemiologic studies were identified that included some mention of adverse events or data collection that occurred â¥28 days post-cessation of tafenoquine
TAFENOQUINE 203 that provided directly relevant information for assessing persistent adverse events (Ackert et al., 2019; Green et al., 2014; Leary et al., 2009; Miller et al., 2013; Nasveld et al., 2010; Rueangweerayut et al., 2017; Walsh et al., 2004). The stud- ies varied in the amount of usable information, so their findings are not weighted equally in drawing conclusions, and epidemiologic evidence was given more weight than supportive information. As described in Chapter 3, the committee considered several methodologic issues in assessing each studyâs contribution to the evidence base on persistent or latent adverse events, including the overall study design, the quality of exposure and health outcome assessment, the ability to address confounding and other potential biases, sample size, and the extent to which the post-cessation health experience was effectively isolated. Six of the studies had strong designs with randomization of participants; four of these were double blinded (Leary et al., 2009; Miller et al., 2013; Nasveld et al., 2010; Walsh et al., 2004), and two (Ackert et al., 2019; Green et al., 2014) were single blinded. Four studies used a placebo-control arm (Ackert et al., 2019; Green et al., 2014; Leary et al., 2009; Walsh et al., 2004). All were considered high-quality studies that contributed to the evidence for the outcomes addressed in the syntheses. The studies are heterogeneous in the populations that were used (active military or veterans, and research volunteers), the numbers of participants (range 51â654), the modes of data collection (administrative records, researcher collected, self-report) on drug exposure, health outcomes and covariates, the type of prophylactic regi- men and dosages used (five studies used off-label dosages of tafenoquine), and, particularly, the nature of the health outcomes that were considered. The relevant studies were also notably inconsistent in the reporting of results, covering different time periods in relation to the cessation of drug exposure. Given the inherently imperfect information generated by any one study, it would be desirable to have similar studies in order to assess the consistency of findings, but the diversity of the studiesâ methods makes it very difficult to combine information across the studies with confidence. For each health outcome category, supporting information from FDA; known concurrent adverse events, including data from selected treatment trials with long-term follow-up; and experimental animal and in vitro studies are first sum- marized, after which the evidence from the post-cessation epidemiologic studies is described. While the charge to the committee was to address persistent and latent adverse events, the occurrence of concurrent adverse events enhances the plau- sibility that problems may persist beyond the period after cessation of drug use. The synthesis of the evidence is followed by a conclusion about the strength of the evidence regarding an association between the use of tafenoquine and persistent or latent adverse events and whether the available evidence would support additional research into those outcomes. The outcomes are presented in the following order: neurologic disorders, psychiatric disorders, gastrointestinal disorders, eye disor- ders, cardiovascular disorders, and other outcomes, which includes renal, hepatic, and hematologic parameters as well as nasopharyngitis.
204 LONG-TERM HEALTH EFFECTS OF ANTIMALARIAL DRUGS The committee believes it is pertinent that FDA is requiring the manufacturer of tafenoquine to conduct two post-approval studies. The first, which is still in its planning stages, is an observational study to evaluate safety, including neurologic, hypersensitivity, psychiatric, and hematologic adverse reactions, in participants taking tafenoquine compared with atovaquone/proguanil. The second, which is currently recruiting participants (NCT #03320174), is a randomized double-blind placebo-controlled study that will administer a loading dose of tafenoquine and 51 weeks of prophylaxis, with long-term follow-up to monitor adverse events. Neurologic Disorders The sources of supporting information that contributed to the evidence base to assess tafenoquine and neurologic disorders were the FDA package insert and briefing document, three malaria-treatment studies, and biologic plausibility stud- ies. The FDA package insert and the FDA briefing document both referred to a safety set of data comprising five studies (FDA, 2018c,d). In a pooled analysis of the safety set, the most common concurrent neurologic adverse reactions (incidence â¥1%) with tafenoquine use were headache, dizziness, and motion sick- ness, although the studies did not conduct systematic monitoring for neurologic symptoms (FDA, 2018c,d). The incidence of headache and lethargy was similar between the tafenoquine group and the mefloquine group, and the incidence of dizziness and vertigo/tinnitus was lower in the tafenoquine group than in the mefloquine group (FDA, 2018c). In a pooled analysis of three studies from the safety set (all with 12â15 weeks of exposure), the incidence of the grouped out- comes of falls, dizziness, and lightheadedness with tafenoquine was higher than for placebo but lower than for mefloquine (FDA, 2018c). In the same analysis, the incidence of headache was found to be similar in the tafenoquine and placebo groups but higher for mefloquine; the incidence of vertigo and tinnitus was 0% for placebo and tafenoquine, and 1.4% for mefloquine. Three malaria-treatment trials (Fukuda et al., 2017; Lacerda et al., 2019; Llanos-Cuentas, 2019) used higher-than-Â rophylactic dosages for 1â3 days and had follow-up periods of p 120â180 days (including the dosage period), although the timing of the adverse events was not distinguished. One study (Fukuda et al., 2017) reported greater frequencies of headache and dizziness with tafenoquine (400 mg for 3 days) than with Â hloroquine/primaquine. The other two studies (Lacerda et al., 2019; Llanos- c Cuentas, 2019) used a single 300 mg tafenoquine dose following chloroquine; one reported a higher frequency of dizziness with chloroquine/tafenoquine versus chloroquine/placebo, and the other an only slightly higher frequency of dizziness with chloroquine/tafenoquine versus chloroquine/primaquine. Biologic plausibility studies of tafenoquine did not support signs of clinical neurologic effects or neurodegeneration or mechanisms of neurologic toxicity or neuropathology, even when supratherapeutic doses were given to rats and rhesus monkeys.
TAFENOQUINE 205 None of the seven epidemiologic studies included data for neurologic adverse events for which timing post-drug-cessation was specified. Based on the available evidence, the committee concludes that there is insuf- ficient or inadequate evidence of an association between the use of tafenoquine 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 Tafenoquine is contraindicated in persons with a history of psychotic disorders or who have current psychotic symptoms. The FDA package insert and the FDA briefing document both referred to a safety set of data comprising five studies (FDA, 2018c,d). In an analysis of the safety set, the most common concurrent psychiatric adverse reactions (incidence â¥1%) were insomnia, depression, abnormal dreams, and anxiety (FDA, 2018d). Individuals with a history of psychiatric disorders were excluded from three of the five studies; those with a history of drug or alcohol abuse were excluded from a fourth. In the safety set, the reported incidences of psychiatric adverse reactions for tafenoquine and mefloquine were similar, but both were higher than with placebo (FDA, 2018c). The incidence of insomnia was higher with tafenoquine than with placebo, which in turn was higher than with Â mefloquine, although the incidence among the three groups was similar. Psychiatric adverse events led to study discontinuation by two participants taking tafenoquine (one suicide attempt; one depression), one taking mefloquine (depression), and none taking placebo. A study in the safety set that included deployed Australian soldiers (Nasveld et al., 2010) reported the incidence of any kind of sleep symp- tom (insomnia, abnormal dreams, sleep disorder, somnambulism) to be similar in the tafenoquine and mefloquine groups (FDA, 2018c), as was the incidence for anxiety, depression, euphoric mood, and agitation. In a different analysis of the same five studies (Novitt-Moreno et al., 2017), after stratifying for deployed or resident status, the occurrence of any psychiatric adverse events was higher in the tafenoquine-deployed group (5.1%) than in the tafenoquine-resident group (2.1%) and the Â lacebo-resident group (1.0%). Only comparisons between the tafenoquine- p deployed group and the tafenoquine-resident group were reported for specific psychiatric adverse events, and the tafenoquine-deployed group had a higher inci- dence of all psychiatric disorders than the tafenoquine-resident group, suggesting a deployment effect on the occurrence of these types of adverse events. A malaria- treatment study reported a slightly higher frequency of insomnia in participants given chloroquine/tafenoquine than in those given chloroquine/primaquine, but the chloroquine/tafenoquine incidence was only 1.2% (Llanos-Cuentas, 2019). Studies of the use of tafenoquine in supratherapeutic doses conducted in rats and rhesus monkeys found no signs of neurologic toxicity. Animal studies
206 LONG-TERM HEALTH EFFECTS OF ANTIMALARIAL DRUGS with tafenoquine do not show the classic brain stem pathology found with earlier 8-Â minoquinolines in rhesus monkeys, even with high doses, but the available a data are limited (60 Degrees Pharmaceuticals, 2018; Berman et al., 2018; Dow et al., 2017). None of the seven epidemiologic studies included data for psychiatric adverse events for which the timing post-drug-cessation was specified. Based on the available evidence, the committee concludes that there is insuf- ficient or inadequate evidence of an association between the use of tafenoquine for malaria prophylaxis and persistent or latent psychiatric events. Current evidence suggests further study of such an association is warranted, given the evidence regarding biologic plausibility, adverse events associated with concurrent use, or findings from the existing epidemiologic studies. Gastrointestinal Disorders The FDA package insert and the FDA briefing document both referred to a safety set of data comprising five studies (FDA, 2018c,d). In a pooled analysis of the safety set, concurrent gastrointestinal adverse reactions with an incidence â¥1% were abdominal pain, upper abdominal pain, constipation, diarrhea, dyspepsia, gastritis, nausea, and vomiting (FDA, 2018c). The incidence of diarrhea and vom- iting was higher with tafenoquine than with mefloquine or placebo (FDA, 2018c). However, in one of the studies in the safety set, carried out in deployed Australian soldiers (Nasveld et al., 2010), the reported incidence of diarrhea, nausea, vomit- ing, and abdominal pain was lower with tafenoquine than with mefloquine (FDA, 2018c). In a different analysis of the same five studies (Novitt-Moreno et al., 2017), after stratifying for deployed or resident status, concurrent adverse events that occurred in both deployed and resident tafenoquine recipients at an incidence â¥1% and at a higher incidence than the placebo-resident group included diarrhea, nausea, vomiting, and gastroenteritis. In comparisons among the tafenoquine- deployed group, the tafenoquine-resident group, and the placebo-resident group, diarrhea (18.1% versus 4.8% versus 3.1%) and gastroenteritis (37.2% versus 7.8% versus 5.8%) were highest in the tafenoquine-deployed group, again suggesting a deployment effect on the occurrence of these types of adverse events. Three malaria-treatment trials (Fukuda et al., 2017; Lacerda et al., 2019; Llanos-Cuentas, 2019) used higher-than-prophylactic dosages for 1â3 days and had follow-up periods of 120â180 days (including dosage period), although tim- ing of the adverse events was not distinguished. One study (Fukuda et al., 2017) reported a greater frequency of nausea, dyspepsia, and diarrhea in tafenoquine- alone recipients than in chloroquine/primaquine recipients. In a second study (Lacerda et al., 2019), vomiting and diarrhea occurred more frequently in the Â hloroquine/tafenoquine group than in the chloroquine/placebo group. In a third c study (Llanos-Cuentas, 2019), vomiting, upper abdominal pain, and Â iarrhea d occurred more frequently in the chloroquine/tafenoquine group than in the
TAFENOQUINE 207 c Â hloroquine/primaquine group. Edstein et al. (2007) found that women who took a 3-day course of tafenoquine 400 mg daily (as a single or split dose) following a course of doxycycline experienced nausea and abdominal distress more than twice as often as men; the difference was statistically significant for the once-daily comparison. Among those who experienced gastrointestinal symptoms, women had higher concentrations of drug 12 hours after the last dose and a significantly lower average body weight than the men. Statistical analysis indicated that women weighing <78 kg in the once-daily group and <64 kg in the split-dose group were likely to experience gastrointestinal effects. No studies were identified that pro- vided information on biologic plausibility for gastrointestinal disorders. None of the seven epidemiologic studies that the committee reviewed included data for gastrointestinal adverse events for which timing post-drug- cessation was specified. Based on the available evidence, the committee concludes that there is insuf- ficient or inadequate evidence of an association between the use of tafenoquine 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 The FDA package insert states that vortex keratopathy was reported in 21â93% of tafenoquine recipients in three trials that included ophthalmic evaluations (Leary et al., 2009; Nasveld et al., 2010; a malaria-treatment trial [NCT #0129060]), but the condition caused no functional visual changes and resolved within 1 year of drug cessation (FDA, 2018d). Retinal abnormalities occurred in less than 1% of tafeno- quine recipients. The FDA briefing document noted that while tafenoquine is associ- ated with reversible vortex keratopathy, the risk of adverse effects on vision and the retina cannot be adequately ascertained based on available data (FDA, 2018c). In an integrated safety study of five clinical trials (Novitt-Moreno et al., 2017), after strati- fying by deployment or resident status, eye disorders were reported to have occurred in 17% of the tafenoquine-deployed group, 10.2% of the tafenoquine-resident group, and 10.5% of the placebo-resident group. Vortex keratopathy represented the majority of the deployed groupâs eye disorders; these reversed after drug cessation and caused no functional vision changes. The identification of the remainder of eye disorders in the deployed group and all eye disorders in the resident groups was not provided. A malaria-treatment trial (Fukuda et al., 2017) of tafenoquine (400 mg for 3 days) versus a chloroquine/primaquine regimen reported vortex keratopathy in 31.8% and retinopathy/retinal disorder in 22.7% of tafenoquine recipients, compared with 0% and 4.2%, respectively, of the Â hloroquine/primaquine recipients. While c there were no clinically relevant effects, possible early retinal morphologic changes were reported in one tafenoquine participant.
208 LONG-TERM HEALTH EFFECTS OF ANTIMALARIAL DRUGS In experimental studies, no tafenoquine-related ophthalmic pathologies have been reported in dogs (Levine, 1997a,b). A 6-month toxicity study in rats showed no treatment-related ophthalmic lesions at week 13 or week 26 (Levine, 1996). Of the seven epidemiologic studies that met inclusion criteria, four studies (Ackert et al., 2019; Leary et al., 2009; Miller et al., 2013; Nasveld et al., 2010) included data for eye-disorder adverse events for which the timing post-drug- cessation was specified. Two studies (Leary et al., 2009; Nasveld et al., 2010) reported a high rate of mild reversible vortex keratopathy (corneal deposits) and no related visual disturbances. All cases resolved while taking the drug or within 3 to 12 months after drug cessation; retinal abnormalities were reported in one case but were not associated with a decrement in visual acuity, foveal sensitivity, or visual field up to 11 months after drug cessation. A study that compared oph- thalmic outcomes in participants taking a single 300 mg dose of tafenoquine or placebo (Ackert et al., 2010) reported no difference in ophthalmic safety between groups. A fourth, small study (Miller et al., 2013) reported a clinically significant reduction in visual acuity in one tafenoquine recipient (450 mg for 2 days) that resolved by day 56. Based on the available evidence, the committee concludes that there is suf- ficient evidence of an association between the use of tafenoquine for malaria prophylaxis and vortex keratopathy, but with unclear clinical significance. There is insufficient or inadequate evidence of an association between the use of tafenoquine for malaria prophylaxis and other persistent or latent eye disorders. Current evidence suggests further study of such an association is warranted, given evidence regarding biologic plausibility, adverse events associated with concur- rent use, or data from the existing epidemiologic studies. Cardiovascular Disorders The FDA package insert states that based on a study of healthy adults who were administered 400 mg tafenoquine (twice the recommended dose) for 3 days, the mean increase in the QTcF interval for tafenoquine was less than 20 ms (FDA, 2018d). The FDA briefing document reports that there were no serious cardiac events reported in tafenoquine recipients in a data set of five trials, and no car- diac adverse events occurred at an incidence â¥1% (FDA, 2018c). Cardiovascular adverse events were not examined or were not reported by sources of supporting evidence (reviews, treatment studies, case report, biologic plausibility studies). Two epidemiologic studies that met the inclusion criteriaâa long-term pro- phylaxis trial (Nasveld et al., 2010) and a dose-ranging safety trial (Green et al., 2014)âassessed cardiac events as primary outcomes, measuring the effects of tafenoquine on QT interval and QTcF, respectively, and reported no evidence of persistent adverse cardiac events.
TAFENOQUINE 209 Based on the available evidence, the committee concludes that there is insuf- ficient or inadequate evidence of an association between the use of tafenoquine 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 Renal In the safety set of five clinical trials referred to by the FDA package insert and FDA briefing document, 0.6% of the tafenoquine group and 0.5% of the placebo group experienced GFR decreases compared with none in the mefloquine group (FDA, 2018c). Creatinine changes occurred in 0.4% of the tafenoquine group, 0.3% of the placebo group, and 1% of the mefloquine group. Mild GFR decreases led to study discontinuation by 0.2% of tafenoquine recipients in one of the safety set studies (Leary et al., 2009), although serum creatinine remained within normal range (FDA, 2018c). A malaria treatment trial (Fukuda et al., 2017) reported that hypokalemia occurred more frequently in tafenoquine-alone recipients (6.5%) than in chloroquine/primaquine recipients (4.2%). Three epidemiologic studies met the inclusion criteria and included data for renal adverse events for which the timing post-drug-cessation was specified (Leary et al., 2009; Nasveld et al., 2010; Walsh et al., 2004). A study in Thai soldiers (Walsh et al., 2004) comparing tafenoquine (400 mg, loading dose and weekly) and placebo reported no differences in renal function between the treatment arms. A study in Australian soldiers (Nasveld et al., 2010) reported that at follow-up, 6â8% of participants in the tafenoquine and mefloquine arms had creatinine values that were 25% above baseline, but few were outside the normal range, and none were clinically significant. In a third study (Leary et al., 2009), clinically important renal findings were reported in the tafenoquine arm (3.6%) and placebo arm (11.5%), but no cases were associated with a significant change in GFR or serum creatinine con- centration, and all resolved without treatment. One tafenoquine recipient showed creatinine phosphokinase values outside the normal range during the follow-up, but further information was not provided. Hepatic In the package insert, in a pooled analysis of a safety set of five trials, increased alanine aminotransferase incidence was reported in â¥1% of tafenoquine recipients (FDA, 2018d). A malaria-treatment trial (Fukuda et al., 2017) reported hepatomegaly more frequently in tafenoquine recipients (6.5%) than in chloro- quine/primaquine recipients (0%). Supertherapeutic doses (400â700 mg/kg) in rats
210 LONG-TERM HEALTH EFFECTS OF ANTIMALARIAL DRUGS were reported to increase liver enzymes (Dow et al., 2017). One epidemiologic study included data for hepatic outcomes for which timing post-drug-cessation was specified (Walsh et al., 2004) and found no differences in hepatic function between Thai soldiers who used tafenoquine 400 mg (loading dose, and weekly for up to 5 months) and those on placebo. Nasopharyngitis An integrated safety analysis of five clinical trials (Novitt-Moreno et al., 2017), after stratifying by deployment and resident status, reported that nasopharyngitis occurred in both the deployed and resident tafenoquine groups at an incidence â¥1% and at a higher incidence than in the placebo-resident group. Further analysis showed a higher incidence of nasopharyngitis in the tafenoquine-deployed group (19.7%) than in the tafenoquine-resident group (3.3%). A malaria-treatment trial (Llanos-Cuentas, 2019) reported nasopharyngitis to occur with greater frequency in the chloroquine/tafenoquine group than in the chloroquine/primaquine group (3.6% versus 2.4%). A case study (Cannon et al., 2015) reported that an individual exposed to airborne powdered tafenoquine in a factory experienced severe Â hinitis, r wheezing, and breathlessness that persisted for several days. Nasopharyngeal adverse events were not examined or not reported in biologic plausibility studies. None of the seven post-cessation epidemiologic studies reported nasopharyngitis as a persistent or latent adverse event. Hematologic Tafenoquine is contraindicated in individuals with G6PD deficiency and in those whose G6PD status is unknown, in breastfeeding women when the infant is G6PD deficient or G6PD status is unknown, and in pregnant women if the status of the fetus is unknown (FDA, 2018d). G6PD testing must be performed before prescribing tafenoquine. The danger of hemolysis and hemolytic anemia in G6PD- deficient persons who use 8-aminoquinolines is well known. Methemoglobinemia, usually mild and reversible, is another well-charac- terized feature of the use of 8-aminoquinolines. The package insert states that tafenoquine is associated with methemoglobinemia and that persons with NADH- dependent methemoglobin reductase deficiency should be monitored during use (FDA, 2018d). Referring to a safety set of five clinical trials, the package insert reports that asymptomatic elevations in methemoglobin occurred in 13% of tafenoquine recipients. Tafenoquine is also associated with decreases in hemo- globin, and decreases â¥3 g/dL were observed in 2.3% of tafenoquine recipients in the safety set. One malaria treatment study reported a greater frequency of methemoglobinemia and thrombocytopenia with a tafenoquine regimen than with a chloroquine/primaquine regimen (Fukuda et al., 2017); other treatment Â tudies s reported a greater frequency of a decline in hemoglobin with a chloroquine/
TAFENOQUINE 211 tafenoquine regimen than with a chloroquine/placebo regimen (5.4% versus 1.5%) (Lacerda et al., 2019) and a chloroquine/primaquine regimen (2.4% versus 1.2%) (Llanos-Â uentas, 2019). A Cochrane review of three earlier malaria treatment trials C reported a dose-dependent asymptomatic rise in methemoglobin in tafenoquine- treated groups (Rajapaske et al., 2015). The biologic plausibility of tafenoquine causing reversible methemoglobin- emia is supported by studies in dogs (Anders et al., 1988). Tafenoquine was shown in vitro to cause methemoglobin formation at a greater rate than primaquine. In mice, tafenoquine blunted platelet response to calcium ions and it increased platelet aggregation, especially with concurrent thrombin exposure (Cao et al., 2017). However, no conclusions were made as to the mechanisms underlying the drugâs effects on platelet apoptosis, and further study is needed of its effects on coagulation. In a study in rats, supertherapeutic doses negatively affected red blood cell parameters (Dow et al., 2017). As an 8-aminoquinoline, tafenoquine-induced hemolysis and toxicity is enhanced in people with G6PD deficiency (Melariri et al., 2015). In an in vitro study, human erythrocytes from healthy volunteers were exposed to tafenoquine at a clinically relevant dose for 48 hours, and tafenoquine was shown to trigger suicidal erythrocyte death (eryptosis). Five epidemiologic studies that met the inclusion criteria included data for hematologic adverse events for which the timing post-drug-cessation was speci- fied. Nasveld et al. (2010) reported that mean methemoglobin levels increased by 1.8% in the tafenoquine group compared with 0.1% in the mefloquine group, but the increases resolved by week 12 of follow-up. Green et al. (2014) reported that tafenoquine at supratherapeutic and therapeutic concentrations prolonged elevations in methemoglobin levels, but without signs or symptoms, and the levels returned to normal by day 63 of follow-up. In Miller et al. (2013), mean methemoglobin measures increased slightly from baseline in the tafenoquine and chloroquine/tafenoquine groups; the greatest increases (>10%) occurred in the chloroquine/tafenoquine group, but these values returned to normal by day 28 and in all cases by day 56. A trend for mild declines (1.5 to 2.5 g dlâ1) in hemoglobin was noted in a greater proportion of tafenoquine-treated subjects than in those treated with chloroquine alone; the greatest decreases (2.8 and 3.0 g dlâ1 on day 10) were seen in two African American women but values returned to baseline by day 56. Walsh et al. (2004) reported that for complete blood counts, there were no significant differences between the mean monthly values of the tafenoquine and placebo groups and no significant changes from baseline values in either group. In a study in women with normal G6PD activity and with heterozygous G6PD defi- ciency, a single dose of tafenoquine (100â300 mg) in the G6PD-deficient group decreased hemoglobin and hematocrit measures but not to dangerous levels; the highest dose of tafenoquine lowered hemoglobin to approximately â3.0 g/dL (Rueangweerayut et al., 2017). The hemolytic potential was dose dependent, and hemolysis was greater in G6PD-heterozygous females with lower G6PD-enzyme activity levels.
212 LONG-TERM HEALTH EFFECTS OF ANTIMALARIAL DRUGS If severe hemolytic anemia is not treated or controlled, it can lead to seri- ous complications, includingÂ arrhythmias,Â cardiomyopathy,Â heart failure, and deathÂ (Baird, 2019; NIH, n.d.).Â Methemoglobinemia can result in decreased avail- ability of oxygen to tissues, and more severe methemoglobinemia can lead to com- plications, including abnormal cardiac rhythms, altered mental status, delirium, seizures, coma, and profound acidosis and death (Denshaw-Burke et al., 2018). Drug-associated hemolysis and methemoglobinemia resolve with withdrawal of exposure to tafenoquine.Â Although the above effects are possible and could cause sequelae that endure beyond the time of exposure, the committee did not identify any published cases of persistent or latent effects resulting from prophylactic doses of tafenoquine. REFERENCES 60 Degrees Pharmaceuticals, LLC. 2018. ArakodaTM (tafenoquine succinate) tablets for the preven- tion of malaria in adults. NDA 210607. Briefing document for the Antimicrobial Drugs Advi- sory Committee, July 26, 2018. AAO (American Academy of Ophthalmology). 2019. Corneal verticillata. https://www.aao.org/bcscs- nippetdetail.aspx?id=27980840-6807-4c45-aaae-b8652b087987 (accessed December 11, 2019). Ackert, J., K., Mohamed, J. S. Slakter, S. El-Harazi, A. Berni, H. Gevorkyan, E. Hardaker, A. H Â ussaini, S. W. Jones, G. C. K. W. Koh, J. Patel, S. Rasmussen, D. S. Kelly, D. E. Baranano, J. T. Thompson, K. A. Warren, R. C. Sergott, J. Tonkyn, A. Wolstenholme, H. Coleman, A. Yuan, S. Duparc, and J. A. Green. 2019. Randomized placebo-controlled trial evaluating the ophthalmic safety of single-dose tafenoquine in healthy volunteers. Drug Saf 42(9):1103-1114. Anders, J. C., Chung, H., and Theoharides. A. D. 1988. Methemoglobin formation resulting from administration of candidate 8-aminoquinoline antiparasitic drugs in the dog. Fundam Appl Toxicol 10(2):270-275. ATGA (Australian Therapeutic Goods Administration). 2019. Australian public assessment report for tafenoquine succinate. https://www.tga.gov.au/sites/default/files/auspar-tafenoquine-succi- nate-190408.docx (accessed December 17, 2019). Australia. 2018. The use of the quinoline anti-malarial drugs mefloquine and tafenoquine in the Aus- tralian Defence Force. December. https://www.aph.gov.au/Parliamentary_Business/Committees/ Senate/Foreign_Affairs_Defence_and_Trade/Mefloquine (accessed November 13, 2019). Australia. n.d. Department of Defence. Tafenoquine FAQs. https://www.defence.gov.au/Health/ HealthPortal/Malaria/AMI_research/tafenoquine-trials/FAQs.asp (accessed November 14, 2019). Baird, J. K. 2018. Tafenoquine for travelersâ malaria: Evidence, rationale and recommendations. J Travel Med 25(1):tay110. Baird,Â J. K. 2019. 8-aminoquinolineÂ therapy for latent malaria. Clin Microbiol Rev 32(4):e00011-19. Berman, J., T. Brown, G. Dow, and S. Toovey. 2018. Tafenoquine and primaquine do not exhibit clinical neurologic signs associated with central nervous system lesions in the same manner as earlier 8-aminoquinolines. Malar J 17(1):407. Bhuyan, A.A.M, R. Bissinger, K. Stockingera, and F. Lang, 2016. Stimulation of suicidal erythrocyte death by tafenoquine. Cell Physiol Biochem 39:2464-2476. Brueckner, R. P., K. C. Lasseter, E. T. Lin, and B. G. Schuster. 1998. First-time-in-humans safety and pharmacokinetics of WR 238605, a new antimalarial. Am J Trop Med Hyg 58:645-649.
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