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8 Primaquine Primaquine, or primaquine phosphate, was synthesized in 1945 at Columbia University under a U.S. government wartime contract (Baird, 2019), but the U.S. Army did not begin large-scale safety and efficacy studies until the early 1950s, when relapsing Plasmodium vivax malaria had emerged as a public health con- cern in troops returning from the Korean War (Kitchen et al., 2006). In 1951, while primaquine was still an experimental drug, the U.S. military performed a randomized placebo-controlled trial on shipboard veterans returning home from Korea (Baird, 2019; Brundage, 2003). The Food and Drug Administration (FDA) approved primaquine for the treatment of P. vivax and P. ovale for military use in January 1952 and for civilian use in August 1952 (Kitchen et al., 2006). The drug was manufactured by Winthrop-Stearns, Inc. (DoD, n.d.a). By 1953 more than 250,000 repatriating service members would receive primaquine, and the drug was credited with preventing the reintroduction of malaria to the United States (Alving et al., 1960). Primaquine continues to be widely used because of the varied activity of the 8-aminoquinoline class. It can kill developing parasites of all Plasmodium spe- cies in the liver, as well as the dormant hypnozoites of P. vivax and P. ovale, the blood schizonts and gametocytes of P. vivax, and the gametocytes of P. falciparum (Â shley et al., 2014; Baird, 2019; Berman, 2004). Thus it can be used as primary A prophylaxis, for radical cure and presumptive anti-relapse therapy, to block human-to-mosquito transmission, and finally, combined with sporozoite inocula- tion, to vaccinate against Plasmodium parasites (Ashley et al., 2014; Baird, 2019; Goh et al., 2019; Schlagenhauf et al., 2019). The role of primaquine in malaria prophylaxis has been singular; until recently it was the only available agent that could eliminate Plasmodium hypnozoites, a life stage of malaria that is unique to 291
292 LONG-TERM HEALTH EFFECTS OF ANTIMALARIAL DRUGS P. vivax and P. ovale. Hypnozoites, which are undetectable by diagnostic tests, can lie dormant in the liver for months to years and then differentiate, traveling to the blood to cause clinical malaria and enable malaria transmission (Ackert et al., 2019; Rishikesh and Saravu, 2016). As an effective hypnozoiticide, primaquine has been of particular value to the U.S. military because P. vivax is endemic, or has been endemic during a military presence, in areas of military operation. Examples include Afghanistan, where P. vivax represents 95% of malaria cases, and Iraq, where the 1990â1991 Gulf War led to a years-long resurgence of P. vivax (CDC, 2019a; Schlagenhauf, 2003). The FDA-approved indication for primaquine reads, âfor the radical cure (pre- vention of relapse) of vivax malariaâ (FDA, 2017a). The term âradical cureâ gen- erally refers to a regimen of a blood schizonticide (e.g., chloroquine) paired with a hypnozoiticide (e.g., primaquine) to treat a confirmed case of malaria by elimi- nating all erythrocytic and hepatic parasites in the body (Baird, 2019; Hill et al., 2006). There is some inconsistency in the literature, however, and the term âradical cureâ has also been used more narrowly to refer to eliminating P. vivaxÂ andÂ P. ovale hypnozoites from the body of an infected individual (CDC, 2019b). The dosage and administration information in the primaquine FDA package insert notes fur- ther that primaquine is recommended âfollowing the termination of chloroquine phosphate suppressive therapy in an area where vivax malaria is endemicâ (FDA, 2017a). The latter recommendation points to the use of primaquine for prophylaxis rather than for treatment. This use of primaquine differs from the way that standard blood-schizonticide antimalarials (e.g., chloroquine, doxycycline, atovoquone/ proguanil, mefloquine) are used for primary prophylaxis. Instead, primaquine is used at or toward the end of primary prophylaxis to kill hypnozoites, which a blood schizonticide used as primary prophylaxis cannot kill (CDC, 2017b; Hill et al., 2006). Presumptive anti-relapse therapy (PART) is a regimen that uses an antimalarial drug to kill hypnozoites and is also referred to as terminal prophy- laxis. As with the term âradical cure,â the term âPARTâ has been used variably in the literature; it has been used both to refer to a component of a regimen to treat confirmed malaria and to a regimen added onto primary prophylaxis to kill hypnozoites (Hill et al., 2006; Vale et al., 2009). The FDA-recommended dosage is 15 mg per day for 14 days (FDA, 2017a). Since the focus of the committee is antimalarial prophylaxis, in this chapter, the term âPARTâ will refer to regimens for prophylaxis and not for treatment of confirmed malaria. The remainder of this chapter follows the same structure as the other antiÂ alarial drug chapters, beginning with a discussion of the FDA package m insert, with a focus on the Contraindications, Warnings, Precautions, and Drug I Â nteractions sections as well as a summary of the changes made to the primaquine package insert since 2003. This is followed by a summary of how the U.S. military has been using primaquine based on Department of Defense (DoD) issuances. A brief overview of the pharmacokinetic properties of primaquine is then provided. The majority of the chapter is focused on adverse events associated with its use for
PRIMAQUINE 293 malaria prophylaxis, beginning with a summary of the known concurrent adverse events associated with primaquine when used as directed for PART. Next, the four identified epidemiologic studies that met the committeeâs inclusion criteria and provided information on persistent or latent health outcomes following the cessation of primaquine are summarized and assessed. These are ordered by popu- lation: studies of military and veterans (U.S. followed by international forces), travelers, and research volunteers. Where available, studies of U.S. participants are presented first. A table that gives a high-level comparison of each of the four epidemiologic studies that examined the use of primaquine and that met the com- mitteeâs inclusion criteria is presented in Appendix C. Supplemental supporting evidence is then presented, including other identified studies of health outcomes in populations that used primaquine for prophylaxis but that did not meet the com- mitteeâs inclusion criteria regarding timing of follow-up; case reports of persistent adverse events associated with primaquine use; and information on adverse events associated with primaquine use in specific groups, such as women and women who are pregnant. After presenting the primary and supplemental evidence in humans, supporting literature from experimental animal and in vitro studies is then sum- marized. The chapter ends with a synthesis of all of the evidence presented and the inferences and conclusions that the committee made from the available evidence. FOOD AND DRUG ADMINISTRATION PACKAGE INSERT FOR PRIMAQUINE This section describes selected information in the FDA label or package insert for primaquine. It begins with information from the most recent label and package insert, detailing contraindications, warnings, and precautions as well as drug interactions known or presumed to occur with concurrent use. It then offers a chronologic overview of the changes made to the label or package insert between 2003 (the earliest label available from the Drugs@FDA Search site) and the most recent label update in November 2017. Contraindications, Warnings, and Precautions The adverse event of greatest concern with primaquine use is hemolysis and the resulting hemolytic anemia in glucose-6-phosphate dehydrogenase (G6PD)- deficient persons (Ashley et al., 2014; Schlagenhauf et al., 2019) (see Chapter 2). The discovery of the link between G6PD deficiencyâthe most common human genetic mutationâand hemolysis emerged in the 1950s during research with primaquine (Chu et al., 2018).The use of primaquine is contraindicated in persons with severe G6PD deficiency (FDA, 2017a). Because the danger of hemolysis in G6PD-deficient persons is well characterized and because primaquine use is contra- indicated in those with severe G6PD deficiency, the committee did not examine the
294 LONG-TERM HEALTH EFFECTS OF ANTIMALARIAL DRUGS evidence of adverse events associated with G6PD deficiency in depth. Primaquine is also contraindicated in patients concurrently receiving other drugs that might cause hemolysis or depress the myeloid elements of the bone marrow. The drug is contraindicated in pregnant women and in acutely ill patients suffering from systemic disease manifested by a tendency to granulocytopenia (e.g., rheumatoid arthritis and lupus erythematosus). Primaquine is contraindicated in those who have recently taken or currently take quinacrine due to the possible potentiation of toxic effects by a structurally related compound. Users are warned of the importance of being tested for G6PD deficiency and screened for a family history of favism prior to use, and they are advised that they should discontinue primaquine if signs of hemolytic anemia occur (FDA, 2017a). Standard screening tests for G6PD deficiency can be inexact; however, both qualita- tive and quantitative point-of-care tests are now being introduced (Baird, 2019; Chu et al., 2018; Pal et al., 2019). The label states that G6PD-deficiency tests have limi- tations and that even in the case of mild to moderate G6PD deficiency, users should consider the risks and benefits of primaquine use. In cases of mild to moderate G6PD deficiency and unknown G6PD status, baseline hematocrit and hemoglobin tests should be performed, hematologic monitoring should be performed at days 3 and 8 of drug use, and adequate medical support to manage hemolytic risk should be available. The label advises sexually active women with reproductive potential to take a pregnancy test before taking the drug and to use contraception during use. A precaution is given against exceeding the dosage (15 mg daily for 14 days) because anemia, methemoglobinemia, and leukopenia have been observed fol- lowing âlarge dosesâ of primaquine (FDA, 2017a). Routine blood examinations in G6PD-normal users are also advised. In addition, due to the potential for QT- interval prolongation with primaquine use, electrocardiogram (ECG) monitoring is advised in patients with cardiac disease, long QT syndrome, a history of ventricu- lar arrhythmias, uncorrected hypokalemia or hypomagnesemia, or bradycardia (<50 bpm). Users are advised that no carcinogenicity and fertility studies have been conducted with primaquine. Drug Interactions Users are advised to use caution when taking primaquine concomitantly with other drugs that prolong the QT interval, and ECG monitoring is recommended for these recipients (FDA, 2017a). Changes to the Primaquine Package Insert Over Time Although the Drugs@FDA Search site lists documentation dating back to primaquine drug approval in 1952, downloadable documentation for primaquine labeling is unavailable for years prior to 2003. The most recent label available on the Drugs@FDA Search site is a June 2017 label (Sanofi-Aventis U.S. LLC) (FDA,
PRIMAQUINE 295 2017b). However, a more recent November 2017 label (Bayshore Pharmaceuticals) is available for download on the U.S. National Library of Medicine DAILYMED site (FDA, 2017a). This is the 2017 label referred to in other sections of the chapter. Although the Drugs@FDA Search site included a web page for documentation for the Bayshore Pharmaceuticals formulation of primaquine, the web page did not list or provide the most recent November 2017 label; the only documentation listed on the web page is dated 2014, and it is unavailable for download. Only those label changes that refer to adverse reactions that occur in adults using primaquine as malaria prophylaxis are reviewed here. The changes to the primaquine label from 2003 to 2017 focused largely on strengthening language about safety concerns in patients with G6PD deficiencies (FDA, 2003, 2008, 2015, 2016, 2017a); as of 2016, routine blood tests are advised during use in G6PD-normal patients. Other updates include adding the potential for cardiac QT- interval prolongation (FDA, 2015) and strengthening warnings against use during pregnancy (FDA, 2017a). The 2017 updates advised caregivers to inform users that nonclinical studies had found evidence of adverse genetic and reproductive effects in pregnant animals and noted that no carcinogenicity or fertility studies had been conducted, but that animal studies suggested that primaquine might hold a human risk for genotoxicity (FDA, 2017a). Since 2003 the Adverse Reactions section has included gastrointestinal and hematologic categories (including met- hemoglobinemia) (FDA, 2003, 2017a), although the source (e.g., clinical trials, postmarketing surveillance) for the symptoms is not stated; a ânervous systemâ category (dizziness) was added in 2016 (FDA, 2016). The 2003 primaquine label contained a boxed warning, sometimes informally referred to as a âblack boxâ (FDA, 2003). This is FDAâs most serious type of warning, and it appears on a prescription drugâs label to call attention to serious or life-threatening risks (FDA, 2012). The boxed warning stated, âPhysicians should completely familiarize themselves with the complete contents of this leaflet before prescribing primaquine phosphateâ (FDA, 2003). The 2015 label did not include the warning box, and the box was absent in the 2016 and June 2017 labels (FDA, 2015, 2016, 2017b). The November 2017 label reintroduced the warning box (FDA, 2017a). POLICIES AND INQUIRIES RELATED TO THE USE OF PRIMAQUINE BY MILITARY FORCES The U.S. military uses primaquine prophylactically as PART in service members who serve in areas endemic for P. vivax or P. ovale (DoD, 2012, 2013a). Primaquine is used for PART more frequently in military service members than in civilian travelers (CDC, 2017b) because the drug is contraindicated in G6PD- deficient persons and requires G6PD-activity testing before use (Baird, 2019).Â If a service member wishes to use primaquine for the off-label purpose of primary
296 LONG-TERM HEALTH EFFECTS OF ANTIMALARIAL DRUGS prophylaxis, an individualized prescription by a licensed medical provider is required.1 During the period 2007â2011, 982 prescriptions for primaquine for pri- mary prophylaxis were written at military facilities (Kersgard and Hickey, 2013). The FDA-approved regimen for radical cure is 15 mg primaquine daily for 14 days (FDA, 2017a). The original 1952 FDA indication was based on clinical trials showing that a 15 mg daily dose could be given without medical supervision to African Americans, who were known to be at higher risk of developing hemolytic anemia at a higher dose, who were returning from the Korean War (Hill et al., 2006). In 2003, based on available evidence, Centers for Disease Control and Prevention (CDC) guidelines recommended that 30 mg of primaquine daily for 14 days be used for PART for prophylaxis (CDC, 2017b).Â In the 2020 Yellow Book, CDC recom- mends that a 30 mg dose be used for 14 days by military service members since nonadherence and inadequate therapeutic dosing (15 mg daily) had led to outbreaks of relapsedÂ P. vivaxÂ malaria in returning personnel (CDC, 2017b). Moreover, the efficacy of a primaquine dose can depend on the strain of malaria species, which vary by geography; certain strains of P. vivax (e.g., the Chesson strain), for example, can require higher doses to eliminate the parasite (Hill et al., 2006). In response to a request to DoD for information about the use of primaquine as malaria prophylaxis in U.S. military service members, the committee received documents that provided information regarding policies for primaquine prophylac- tic use and G6PD-deficiency testing as well as about the policy and recommenda- tions for primaquine dosages for PART. Under the authority of force health protection (see Chapter 2) in deploying military service members, the U.S. military enforces only the FDA-approved labeled use of primaquine for PART (15 mg daily for 14 days).2,3 The Armed Forces Epidemiology Board has recommended the use of a 30 mg dose for PART (DoD, 2003a), as has a 2019 Defense Health Agency issuance (DoD, 2019), but because the dosage remains off label, it is not enforced. A service member can be prescribed an off-label dose of primaquine (e.g., 30 mg per day) if a health care provider recommends it (based on patient interaction, including post-deployment interview from an endemic country where PART is indicated) and the service member provides consent.4 1â Personal communication to the committee, COL Andrew Wiesen, M.D., M.P.H., Director, Preven- tive Medicine, Health Readiness Policy, and Oversight, Office of the Assistant Secretary of Defense (Health Affairs), DoD, September 27, 2019. 2â Personal communication to the committee, COL Andrew Wiesen, M.D., M.P.H., Director, Preven- tive Medicine, Health Readiness Policy, and Oversight, Office of the Assistant Secretary of Defense (Health Affairs), DoD, August 22, 2019. 3â Personal communication to the committee, COL Andrew Wiesen, M.D., M.P.H., Director, Preven- tive Medicine, Health Readiness Policy, and Oversight, Office of the Assistant Secretary of Defense (Health Affairs), DoD, September 27, 2019. 4â Personal communication to the committee, COL Andrew Wiesen, M.D., M.P.H., Director, Preven- tive Medicine, Health Readiness Policy, and Oversight, Office of the Assistant Secretary of Defense (Health Affairs), DoD, August 22, 2019.
PRIMAQUINE 297 The earliest policy document provided to the committee by DoD that refers to prophylactic use of primaquine by U.S. military service members is a 2001 U.S. Central Command (CENTCOM) issuance stating that âterminal prophylaxis with primaquine is indicated for all countries in the CENTCOM area of responsibil- ity where P. vivax and P. ovale malaria are transmitted and where prophylaxis is administered unless specifically stated by local component/Command Joint Task Force guidancesâ (DoD, 2001). CENTCOM covers 20Â countries, includ- ing Afghanistan, Iran, Iraq, Pakistan, theÂ countriesÂ of the Arabian Peninsula and northern Red Sea, and the five republics of Central Asia (DoD, n.d.b). Similarly, a 2006 DoD memorandum to the Third Army states that service members traveling âfor even one dayâ to areas of operation (Afghanistan, Djibouti, Eritrea, Ethiopia, Kenya, Â akistan, Seychelles, Somalia, Sudan, and Uzbekistan) âmust receive P terminal malaria prophylaxisâ (DoD, 2006). A 2013 DoD memorandum states that PART should be provided âwhen clinically and epidemiologically indicatedâ (DoD, 2013b). DoD makes changes to malaria prophylaxis policy as circumstances change. For instance, a 2003 issuance stated that terminal malaria prophylaxis âis no longer requiredâ in Iraq (DoD, 2003b), presumably because intelligence had determined that control over malaria had been regained. This was followed by a DoD policy memorandum stating, âU.S. personnel in Iraq will not take malaria chemoprophy- lactic medicationâ (DoD, 2003c). The U.S. military sets policy that requires G6PD-deficiency testing to be performed in service members who use primaquine. A 2001 CENTCOM issuance states that testing for G6PD deficiency âwill be performed prior to prescription of primaquine in accordance with service policyâ (DoD, 2001). A 2006 DoD memorandum states that âArmy policy now requires all soldiers to be tested for G6PD before deploymentâ (DoD, 2006). The memo notes further that âuntil G6PD screening of deploying CFLCC [Coalition Forces Land Component Command] personnel becomes reliable and routine,â those taking primary prophylaxis will do so for 1 month after returning to a home station; during the first 2 weeks of that month, they will be tested for G6PD deficiency, and PART can be initiated. A 2012 issuance noted that PART will be prescribed only after proper screening and counseling to minimize the risk of adverse reactions (DoD, 2012). In 2003 a DoD memorandum addressing antimalarials was issued by the Armed Forces Epidemiological Board (DoD, 2003a). The authors note first that DoD is subject to Section 1107 of Title 10, United States Code, regarding off- label use of force health protection medications. It then states that this would limit the prescription of CDC-recommended off-label prophylactic regimens (primary prophylaxis and PART) to the context of a doctorâpatient relationship or an inves- tigational new drug protocol, both of which could be problematic in a military setting. In its findings and recommendations, the board states that it finds the CDC consensus guidelines for malaria prevention âappropriateâ for use by DoD and that as G6PD deficiency is a contraindication for primaquine, the documentation of a
298 LONG-TERM HEALTH EFFECTS OF ANTIMALARIAL DRUGS normal G6PD level should be available before the recommended 30 mg dosage is prescribed (DoD, 2003a). DoD also provided the draft of a letter to the Journal of the American Medical Association (directed to authors of an article [Chen et al., 2007]) pointing out that the authors had not recommended an alternative PART regimen for those who are G6PD deficient, in whom a primaquine 30 mg daily dosage would be inappropri- ate (DoD, 2007). Though not explicit, this suggests that some service members may be using the 30 mg dosage. However, DoD issuances dating after 2003 refer only to the use of a 15 mg PART dosing regimen for force health protection (DoD, 2006, 2012). The letter to the medical journal also referred to two cases of G6PD-deficient African American service members who, after being informed of the risks and ben- efits of taking primaquine, elected to take primaquine 15 mg daily and experienced no adverse reactions (DoD, 2007). An individual provider can make a clinical deci- sion to prescribe primaquine to a G6PD-deficient military service member after weighing the risks and benefits (e.g., the risk of relapse may be high).5 However, the service member must provide consent, and the appropriate safety monitoring must be in place. PHARMACOKINETICS Primaquine is rapidly absorbed in the gastrointestinal tract and is extensively distributed in tissues, with a mean volume of distribution of 3 L/kg (Baird and Hoffman, 2004). Absorption is linear with doses of 15 to 45 mg/kg (Hill et al., 2006). The elimination half-life of primaquine ranges from 4 to 9 hours (Baird and Hoffman, 2004; Myint et al., 2011). After a single 45 mg dose of primaquine, the peak serum concentration ranges from 0.13 to 0.18 Âµg/mL (Hill et al., 2006; Myint et al., 2011). After the administration of a 30 mg daily dose of primaquine (base) for 14 days, compared with men women had significantly higher peak serum concentrations (0.21 versus 0.12 Âµg/mL) and total drug exposure values (1.9 ver- sus 0.92 Âµg h/mL) (Binh et al., 2009); thus, the authors suggest that women may be at an increased risk for toxicity compared with men. As reviewed by Hill et al. (2006), most authorities recommend that primaquine be given with food or after a meal to avoid gastrointestinal adverse events, especially abdominal cramps. Primaquine is extensively metabolized (Baird, 2019; Thillainayagam and Ramaiah, 2016). Carboxyprimaquine is the major and inactive metabolite formed by the action of monoamine oxidase (Fasinu et al., 2014; Hill et al., 2006), and the level remains 10-fold higher than that of the parent drug (Hill et al., 2006). 5-Hydroxyprimaquine, formed by CYP450, primarily the CYP2D6 isoform 5â Personal communication to the committee, COL Andrew Wiesen, M.D., M.P.H., Director, Preven- tive Medicine, Health Readiness Policy, and Oversight, Office of the Assistant Secretary of Defense (Health Affairs), DoD, September 27, 2019.
PRIMAQUINE 299 (Camarda et al., 2019; Pybus et al., 2013), is the redox-active metabolite associated with the antimalarial activity of primaquine. ADVERSE EVENTS This section begins with a summary of the known concurrent adverse events of primaquine, such as those that occur immediately or within a few hours or days of taking a dose of the drug. Epidemiologic studies of persistent or latent health effects in which information was available at least 28 days post-primaquine- cessation are then summarized by population category (military or veterans, travelers, and research volunteers), with an emphasis on reported results of per- sistent or latent events associated with use of primaquine (even if results on other antimalarial-drug comparison groups were presented). Concurrent Adverse Events A Cochrane review of mass drug administration for malaria prophylaxis examined 32 studies, but this review was not considered by the committee because only four studies included primaquine, there was no active adverse event surveil- lance in three of the four studies, and no meta-analysis was performed (Poirot et al., 2013). The committee identified one systematic review of primaquine used prophylactically that examined safety (Kolifarhood et al., 2017); this review is discussed below, along with findings from several non-systematic review papers. Kolifarhood et al. (2017) assessed primaquine as compared with other malaria prophylactic drugs or placebo in healthy travelers. The primary outcome was confirmed parasitemia. The secondary outcome was adverse events, including both clinical and laboratory-measured events. Clinical events were categorized as neuroÂ sychiatric and gastrointestinal complaints using the Uppsala Monitor- p ing Center organ system classification of adverse drug reactions. Seven studies included a total of 1,710 participants from 7 to 65 years of age who had been pre- screened for G6PD deficiency. The review included five randomized controlled trials, one nonrandomized trial, and one uncontrolled before-and-after (used base- line measures as comparison) study. Only one study (Schwartz and Regev-Yochay, 1999) included in this review was also included in the final set of epidemiologic studies with long-term follow-up that the committee considered fully. The authors computed incidence rate ratios for individual studies; they did not pool the study data for the safety outcomes (Kolifarhood et al., 2017). For the four trials that included a placebo arm, the authors found no statistically significant difference in relative risk between primaquine and placebo for gastrointestinal adverse events or for neuropsychiatric adverse events (reported in three of the four trials). Comparisons of primaquine with mefloquine, doxycycline, proguanil, and atovaquone/proguanil found no statistically significant difference in incidence
300 LONG-TERM HEALTH EFFECTS OF ANTIMALARIAL DRUGS rates for gastrointestinal or neuropsychiatric adverse events. In one assessed study (Baird et al., 1995), more gastrointestinal and neuropsychiatric adverse events were reported for chloroquine than for primaquine (RR = 4.13, 95%CI 1.83â9.31 and RR = 7.89, 95%CI 3.62â17.2, respectively). In another assessed study (Â asveld et al., 2002), more gastrointestinal adverse events were reported N for tafenoquine than for primaquine (RR = 2.7, 95%CI 1.34â5.42). Non-systematic reviews show that the most serious safety concern with the use of primaquine is the potential for hemolysis in persons with G6PD deficiency (Ashley et al., 2014; Hill et al., 2006; Schlagenhauf et al., 2019), an association that was recognized during its early use (Kitchen et al., 2006) and specifically defined soon after (Dern et al., 1954). Standard guidelines call for testing for G6PD defi- ciency before using primaquine (CDC, 2017a; DoD, 2012; FDA, 2017a). Because of primaquineâs short half-life (4â9 hours) (Baird and Hoffman, 2004; Myint et al., 2011), halting the drug can quickly decrease the drug-induced hemolysisâa fact that highlights the benefit of monitoring primaquine recipients and having medical support available during use (Rishikesh et al., 2016). 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.). Released hemoglobin can also cause damage to the kidney (Ashley et al., 2014). A common occurrence in both G6PD-normal and G6PD-deficient recipients is a mild, reversible methemoglobinemia, a condition that interferes with the ability of the blood to carry oxygen (Baird, 2019; Hill et al., 2006; Rishikesh and Saravu, 2016). Persons who are deficient in the enzyme nicotinamide adenine dinucleotide (NADH) methemoglobin reductase are extremely sensitive to prima- quine (Hill et al., 2006), and if they use primaquine they should be monitored for tolerance (FDA, 2017a). High levels of methemoglobin (>15%) in red blood cells 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 (Denshaw-Burke et al., 2018). Methemoglobinemia in otherwise healthy persons is generally asymptomatic; symptoms such as cyanosis, dizziness, or dyspnea should prompt testing for methemoglobin levels (Hill et al., 2006, Schlagenhauf et al., 2019). The most common adverse event in primaquine users is minor gastroÂntestinal i upset if the drug is taken on an empty stomach (Baird, 2019; Hill et al., 2006; Schlagenhauf et al., 2019). The risk of adverse gastrointestinal events increases with increasing doses of primaquine (Hill et al., 2006), and epidemiologic Â tudies show s these may include abdominal cramps, nausea, epigastric pain, vomiting, and diarrhea (Baird et al., 2001; Ebringer et al., 2011; Nasveld et al., 2002; Soto et al., 1998). Other adverse events include headache, anorexia, skin rash, and itching (NIH, 2017). There is little mention in the literature of primaquine in association with neuroÂ sychiatric events. Three reviews stated that neuropsychiatric symptoms p have been reported rarely with primaquine use (Ashley et al., 2014; Castelli et al., 2010; Hill et al., 2006). Two reviews (Castelli et al., 2010; Hill et al., 2006)
PRIMAQUINE 301 alluded to a single case report of depression and psychosis with primaquine use. The case report described a man who experienced depression, confusion, and anorexia after being treated for malaria (Schlossberg, 1980). There is no mention of neuroÂ sychiatric events in the FDA package insert (FDA, 2017a). p Post-Cessation Adverse Events A total of 1,337 abstracts or titles were identified by the committee for inclu- sion for primaquine. After screening, 558 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 25 primary epidemiologic studies that presented infor- mation indicating that the study population was followed for at least 28 days. Upon further examination, the committee found that 21 of the 25 articles did not include a comparator, did not provide information on adverse events that occurred â¥28 days after cessation of primaquine, or presented data that did not distinguish between adverse events that occurred during the use of primaquine, Ë28 days post-cessation of primaquine, or â¥28 days post-cessation of primaquine. These are briefly discussed later in the chapter under the heading Other Identified Â tudies S of Primaquine Prophylaxis in Human Populations. There were four remaining epidemiologic studies that included some mention of adverse events that occurred â¥28 days post-cessation of primaquine (Nasveld et al., 2010; Rueangweerayut et al., 2017; Schneiderman et al., 2018; Schwartz and Regev-Yochay, 1999), and these 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 these four epidemiologic studies is presented in Appendix C. Primaquine is used as PART (within label) and as primary prophylaxis (off label). The committee sought to review any studies that could inform its under- standing of the drugâs safety when used as prophylaxis; thus, while the committee examined studies using PART, it also considered studies that investigated prophy- lactic regimens that are off label. Two studies in the final data set used primaquine regimens that are not within current FDA labeling. Nasveld et al. (2010) used primaquine as PART, but the dosage (30 mg daily for 2 weeks) was off label. Schwartz and Regev-Yochay (1999) used primaquine as primary prophylaxis. Military and Veterans Schneiderman et al. (2018) conducted a retrospective observational analysis of self-reported health outcomes associated with the use of antimalarial drugs in a cohort of U.S. veterans who had responded to the 2009â2011 National Health Study for a New Generation of U.S. Veterans (referred to as the âNewGen Studyâ). The NewGen Study is a population-based survey that sampled 30,000 veterans who had been deployed to Iraq or Afghanistan between 2001 and 2008 and 30,000
302 LONG-TERM HEALTH EFFECTS OF ANTIMALARIAL DRUGS nondeployed veterans who had served during the same time period, and it included a 20% oversampling of women. The survey was conducted using mail, telephone, and web-based collection and yielded a response rate of only 34.3%. For this particular analysis, 19,487 participants were included who had self-reported their history of antimalarial medication use, and the use was grouped for analysis by drug (mefloquine, chloroquine, doxycycline, primaquine, mefloquine in combina- tion with other drugs, other antimalarials, and not specified) or no antimalarial use. Health outcomes were self-reported using standardized instruments: the Medical Outcomes Study 12-item Short Form (SF-12) for general health status, PTSD ChecklistâCivilian version, and the Patient Health Questionnaire. These instru- ments yielded scores that were dichotomized for analysis on composite physical health, composite mental health (above or below the U.S. mean), posttraumatic stress disorder (PTSD) (above or below screening cutoff), thoughts of death or self-harm, other anxiety disorders, and major depression. Potential confounders included in the multivariable analysis were branch of service, sex, age, educa- tion, race/ethnicity, household income, employment status, marital status, and self-reported exposure to combat. Responses were weighted to account for survey non-response. Most veterans reported no antimalarial drug exposures (61.4%, n = 11,100), and these served as the referent group. When stratified by deployment status, among the deployed (n = 12,456), of those who reported the use of an antimalarial drug (n = 6,650) only 98 (weighted 1.4%) veterans reported using pri- maquine alone, and 425 (weighted 6.0%) reported using mefloquine plus another antimalarial, which may have included primaquine. Among the nondeployed (n = 7,031), 1,737 reported using an antimalarial drug, and of this group only 35 (weighted 1.6%) used primaquine alone, and 52 (weighted 2.8%) used mefloquine plus another antimalarial, which may have included primaquine. Because it is not clear how many people in the mefloquine-plus group may have also used prima- quine, the results of that group are not included in the committeeâs assessment. When comparing outcomes among the deployed group, participants using primaquine alone reported the lowest prevalence of adverse mental and physical health outcomes among the antimalarial regimens: SF-12 mental health compo- nent scores below the U.S. mean (41.0%), SF-12 physical health component scores below the U.S. mean (28.7%), positive screens for PTSD (6.9%), thoughts of death or self-harm (6.3%), other anxiety disorders (1.4%), and major depression (3.3%). Descriptive statistics indicated that, compared with nondeployed primaquine-only users, the deployed primaquine users reported increased frequencies of positive PTSD screens (6.9% versus 3.0%); similar reported frequencies of SF-12 mental health scores below the U.S. mean (41.0% versus 40.7%), thoughts of death or self harm (6.3% versus 5.9%), and symptoms of major depression (3.3% versus 3.2%); and lower frequencies of SF-12 physical health scores below the U.S. mean (28.7% versus 42.8%) and other anxiety disorders (1.4% versus 11.0%). However, no statistical measures were presented. In the adjusted logistic regres- sion models with all covariates considered (including demographics, deployment,
PRIMAQUINE 303 and combat exposure), the use of primaquine alone was not associated with four of the health outcomes as compared with nonuse of antimalarial drugs: composite mental health score (OR = 0.74, 95%CI 0.46â1.18), PTSD (OR = 0.48, 95%CI 0.21â1.10), thoughts of death or self-harm (OR = 0.78, 95%CI 0.31â1.98), and major depression (OR = 0.46, 95%CI 0.17â1.21). The composite physical health score (OR = 0.56, 95% CI 0.35â0.87) was statistically significantly lowerâan indication of better physical healthâfor primaquine users compared with nonÂ users of antimalarial drugs after including demographics, deployment, and combat exposure in the model. The presence of other anxiety disorders (OR = 0.19, 95% CI 0.06â0.67) was statistically significantly lower for primaquine users than for nonusers of antimalarial drugs after including demographics, deployment, and combat exposure in the model. In a stratified analysis, primaquine was associated with a decreased risk of anxiety in the deployed (OR = 0.14, 95%CI 0.03â0.60), but not in the nondeployed (OR = 1.45, 95%CI 0.35â6.08). Although the study was large, the number of primaquine-only users was small, yielding imprecise effect estimates for this exposure. The outcomes were based on standardized instruments (although not face-to-face diagnostic interviews), impor- tant covariates of deployment and combat exposure were considered in addition to demographics and other military characteristics, and the data were appropriately analyzed. The small number of primaquine-only users in this sample (weighted 1.4% of deployed and weighted 1.6% of nondeployed antimalarial users), coupled with the very low odds ratios for physical health and anxiety, raises concerns about the comparability of this group to nonusers of antimalarials and about the validity of associated estimates. As primaquine is commonly used prophylactically by the U.S. military in combination with other drugs (at the end of malaria exposure), it is unknown whether primaquine was actually used alone. It is noteworthy that adjusting for combat exposure consistently reduced the measures of association, potentially indicating that a strong confounding can exist due to combat exposure. Although the time period of drug use and the timing of health outcomes were not directly addressed, given that the populations were all veterans who had served between 2001 and 2008 and that the survey was not administered until 2009â2011, it is reasonable to assume that antimalarial drug use had ceased some time before. Nonetheless, the study could not address explicitly the health experiences dur- ing use and in specific time intervals following the cessation of use. There are a number of methodologic concerns that limit the strength of this studyâs findings. The very small sample size of the primaquine drug category raises questions about generalizability and validity. The low response rate of 34% raises concerns about non-response bias, but responses were weighted to account for this. Selective par- ticipation by both antimalarial drug use history and health status would be required to introduce bias. The accuracy of self-reported antimalarial drug use in this population is unknown. Although self-reported information has some advantages over studies based on prescriptions because self-report implies that the individual recalls using the drug, the reported drug and the information on adherence to that
304 LONG-TERM HEALTH EFFECTS OF ANTIMALARIAL DRUGS drug were not validated. Self-reported health experience is subject to the usual dis- advantages of recall bias and to the bias of reporting subjective experience without independent expert assessment; however, by using standardized assessment tools, these biases may have been circumvented to some extent. Nasveld et al. (2010) conducted a randomized double-blind controlled study to compare the safety and tolerability of mefloquine for 26 weeks (primary pro- phylaxis) followed by primaquine (30 mg per day) for 2 weeks (PART) (n = 162) with the safety and tolerability of tafenoquine for 26 weeks followed by placebo for 2 weeks (n = 492) in male and female Australian soldiers aged 18â55 years. Since tafenoquine is an 8-aminoquinoline with antihypnozoite action (like primaquine), the tafenoquine arm did not require PART and used placebo to preserve study blind- ing. The primaquine dose was off label; the FDA-approved dose is 15 mg per day (FDA, 2017a). 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 examination with normal hemato- logical and biochemical values and also judged 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 contracep- tion. A subset of 98 participants (21 mefloquine/primaquine group, 77 tafenoquine/ placebo group) underwent extra safety assessments to investigate drug-induced p Â hospholipidosis and methemoglobinemia as well as ophthalmic and cardiac safety. In addition to assessments done while taking the medication, the safety group had safety and tolerability assessment, including of hematologic and blood chemistry parameters, at week 2 and at week 12 during the follow-up phase after the last dose of primaquine or placebo. There was an additional telephone follow-up at weeks 18 and 24 post-drug-cessation. Adverse-event monitoring was supplemented by a review of the subjectsâ medical records. In the safety group, mean methemoglobin levels increased by 0.1% in the mefloquine primary-prophylaxis group and by 1.8% in the tafenoquine primary-prophylaxis group, but these increases resolved by week 12 of follow-up (after the primaquine/placebo stage of the study). A small increase in QT interval was seen in the mefloquine followed by primaquine recipients, and a small reduction in mean QT interval was seen in the tafenoquine recipients; 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. Corneal deposits were not observed in any mefloquine primary-prophylaxis recipients in the safety group, so ophthalmic assessment was not performed in these participants after they took the primaquine. The authors stated that during the relapse follow-up phase, 53 (33.9%) of the mefloquine/primaquine subjects and 203 (41.3%) of the Âafenoquine/placebo t 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. The authors do state that at follow-up, 6â8% of the partici- pants 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.
PRIMAQUINE 305 Although the overall study design was rigorous, with randomization of the medications, a temporal ordering of the exposures and outcomes, systematic data collection, high adherence to assigned medications, little attrition from the study (94% of subjects in both arms completed the trial), a placebo control for the anti- hypnozoite (primaquine) stage of the study, and a study population that was highly relevant for the committeeâs task, still the study is limited in the information it provides with respect to persistent or latent adverse events for primaquine because of the limited information it provided about adverse events. Moreover, because the drug regimen involved the sequential use of mefloquine and primaquine, it is dif- ficult to identify what, if any, role an individual drug played in the occurrence of an adverse event. Exposure assessment was fairly strong because of the consistent measurement across the arms and the use of medication logs to measure adherence prospectively. Most adverse events were not assessed in a systematic way, however, limiting the quality of these measures, and the timing of the adverse events was not clearly specified beyond the prophylaxis-use phase, and therefore it was not possible to ascertain how long the adverse events persisted. While the statistical power was sufficient for the primary goal of the study, which was to assess the antimalarial efficacy of the drugs, the sample size was insufficient for assessing the occurrence of most adverse events. In the small safety subgroup, there were no persistent adverse methemoglobin or cardiac outcomes in either group at 12 weeks. Given that there were no adverse ophthalmic outcomes during mefloquine use in the safety subgroup, these outcomes were not assessed during or following the 2 weeks of primaquine. There were no other evaluations of specific adverse outcomes. Travelers Schwartz and Regev-Yochay (1999) performed a prospective observational study, and followed 158 male and female Israeli travelers aged 22â65 years who took part in rafting trips on the Omo River, Ethiopia, and who had visited a travel clinic to obtain malaria prophylaxis. The travelers were prescribed mefloquine, primaquine (15 mg daily for those â¤70 kg; 30 mg daily for those >70 kg), doxycy- cline, or hydroxychloroquine by travel group. The primary aim of the study was to assess incident malaria and to compare the effectiveness of these four antimalarial drugs against both P. falciparum and P. vivax. The primaquine recipients (n = 106) received G6PD-deficiency testing beforehand. The travelers were followed from the time of their return to Israel for an average of 16.6 months (range 8â37 months) for incident malaria. A survey (completed by 50 of the 106 primaquine users) was used to gather information on the travelersâ adherence to the prophylactic regimens and on the adverse events they experienced. Using primaquine for primary pro- phylaxis and at a dose >15 mg per day is not FDA approved. The authors reported that âno severe side effectsâ were reported in any of the travelers. One participant discontinued primaquine because of nausea and vomiting soon after beginning the drug. The strengths of this study include that it used standard recommended
306 LONG-TERM HEALTH EFFECTS OF ANTIMALARIAL DRUGS prophylactic drugs as comparators and that it had a long follow-up (an average of 16.6 months after return from a malaria-endemic country). It was limited by its small sample size, its nonrandomized design, and the lack of details it provided on adverse events. Although a long-term follow-up was completed to assess effective- ness, it is unclear whether specific persistent or latent adverse events would have been reported during this period. As a result, this study provides limited informa- tion that can be used for inference. Research Volunteers Rueangweerayut et al. (2017) used a prospective observational study design to examine the tolerability of primaquine (15 mg for 14 days) compared with tafeno- quine (100, 200, or 300 mg, single dose) in healthy Thai females who were het- erozygous for Mahidol variant G6PD deficiency (primaquine, n = 5; tafenoquine, n = 19) or G6PD normal (primaquine, n = 6; tafenoquine, n = 18). The primary outcome was a maximum absolute decrease in hemoglobin or hematocrit from pre- treatment up to day 14 after treatment. Additional outpatient follow-up visits were at days 21, 28, and 56. In the primaquine group the G6PD-deficient participants completed 6 (2 recipients), 9, 10, and 14 days of treatment; all participants in the G6PD-normal group received 14 days of treatment. Safety assessments included adverse event monitoring, vital signs, 12-lead ECGs, clinical biochemistry, hema- tology (including methemoglobin determined by oximetry), and urinalysis. In the G6PD-deficient arms, dose-limiting adverse effects were reported to occur in 3 of 5 of the primaquine arm, and 3 of 3 of the highest-dose (300 mg) tafenoquine arm; of these, two recipients of each drug experienced both a decrease â¥2.5 g/dL in hemo- globin and a decrease â¥7.5% in hematocrit versus pretreatment. Among the prima- quine recipients, 4 of 6 of the G6PD-normal group showed sustained elevations in methemoglobin (maximum values 5.5â13.1%); values did not exceed 3.9% in the G6PD-deficient group. No tafenoquine recipient experienced methemoglobin levels >5.0%.Â 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 All values appeared to be in the normal range by day 28 (14 days post-drug-cessation). The study was limited by its small sample size and by the narrow range of measures it examined.Â In addition, although the final follow-up visit at day 56 met the inclusion criteria of â¥28 days following drug cessation, there was no information reported from that visit. OTHER IDENTIFIED STUDIES OF PRIMAQUINE PROPHYLAXIS IN HUMAN POPULATIONS Five additional studies of primaquine use in military service members were reviewed by the committee, including studies from Canada (Paul et al., 2003),
PRIMAQUINE 307 Australia (Ebringer et al., 2011; Nasveld et al., 2002), and Colombia (Soto et al., 1998, 1999). However, because they did not follow the military cohorts for at least 28 days after primaquine cessation or did not report on adverse events that occurred post-cessation, these studies were excluded. In addition, an early study in U.S. troops (Vivona et al., 1961) was excluded because the regimen used the âC-P pill,â a combination of chloroquine and primaquine that has not been used for several decades and thus was not reviewed by the committee. Three studies of mass drug administration were reviewed but were excluded because the drug combination (primaquine and an artemisinin) is not one that is used by the population of interest (military service members or veterans) (Landier et al., 2018; Song et al., 2010) or for the lack of a comparator (Tseroni et al., 2015). Eleven remaining studies in various populations were reviewed but were excluded because they did not include a comparator, did not follow the partici- pants after primaquine cessation, did not report on adverse events that occurred post-cessation, or did not distinguish events occurring post-cessation from those occurring while taking the drug (Baird et al., 1995, 2001; Brito-Sousa et al., 2019; Chen et al., 2018; Chinn and Redmond, 1954; Fryauff et al., 1995, 1996; G Â rimmond and Cameron, 1984; Hanboonkunupakarn et al., 2014; Manning et al., Â 2018; Sharafeldin et al., 2010; Winkler, 1970). Case Reports The committee reviewed six published case reports involving primaquine used prophylactically. Most focused on hemolysis in persons with G6PD deficiency, and since this safety concern is well characterized and primaquine is contraindicated in people with severe G6PD deficiency, these were not reviewed in depth. Only one case report met the criterion of following the person for â¥28 days after prima- quine cessation (Kotwal et al., 2009). The patient had taken doxycycline 100 mg daily for malaria prophylaxis before, during, and after a 3-month deployment to Afghanistan, and he took primaquine 15 mg daily concomitantly during the last 14 days of his doxycycline regimen. A month after completing the medications, the patient developed non-ischemic central retinal vein occlusion, and he continued to have mild disk and macular edema with mild vascular defects and hemorrhages after 2 years of treatment for the eye disorder. Subsequent to the development of ocular symptoms, the patient was found to have G6PD deficiency, and the authors suggest hemolysis may have contributed to diffuse microvascular thrombosis that included the eye. However, whether the central retinal vein occlusion was a result of the primaquine use remains uncertain. Selected Subpopulations There is little information in the literature on the use of primaquine used pro- phylactically in selected risk groups.
308 LONG-TERM HEALTH EFFECTS OF ANTIMALARIAL DRUGS Sex Differences A difference between women and men in the reported incidence of adverse events has been observed. In an open-label randomized study in Australian Defence Force members, Nasveld et al. (2002) compared primaquine (22.5 mg daily for 14 days) with tafenoquine (400 mg daily for 3 days) for post-deployment PART. The primaquine dose was not within FDA labeling nor was the tafenoquine dose. The volunteers also took routine doxycycline prophylaxis (100 mg daily) before and concomitantly with the PART regimens. In the doxycycline/primaquine group (women, n = 23; men, n = 193), 8 women (35%) reported nausea, compared with 22 men (12%), and 2 women (9%) reported lethargy, compared with 8 men (4%). Pregnancy Whether primaquine can be used safely during pregnancy has not been estab- lished. Primaquine is contraindicated in pregnancy (FDA, 2017a). Transplacental transfer of primaquine to a G6PD-deficient fetus potentially could result in life- threatening hemolytic anemia in utero. Even if a pregnant woman is G6PD normal, the fetus may not be. CDC guidelines state that primaquine cannot be used by pregnant women (CDC, 2017a). According to the package insert, animal data show reproduction-related toxicity. Nonclinical data from studies conducted in pregnant animals treated with primaquine show evidence of teratogenicity as well as injury to embryos and developing fetuses (FDA, 2017a). BIOLOGIC PLAUSIBILITY There are relatively few reports assessing primaquine effects on neuronal func- tion. Very high (toxic) doses of primaquine can induce cell loss in brain regions con- trolling neuroendocrine (paraventricular and supraoptic nuclei) and cardiovascular function (dorsal motor nucleus of the vagus) in non-human primates, according to an early study (Schmidt and Schmidt, 1951). The authors of that study stated that âthere is little likelihood that significant neuronal injury would result from clinical use of â¦ primaquine â¦ in doses such as are applied in malaria therapy.â Hypotension, cardiac contractility, and arrhythmias can be observed upon administration of toxic doses of primaquine in rats and dogs (Bass et al., 1972; Orta-Salazar et al., 2002). Cardiac effects can be linked to the blockade of sodium channels in cardiomyocytes, which results in decreased contractility (Orta-Salazar et al., 2002). Primaquine also blocks the delayed rectifier hERG potassium chan- nels in HEK293 cells, resulting in effects that may be linked to the prolonged QT intervals or arrhythmias that occur in some individuals after taking antimalarials (Kim et al., 2010). Like other members of the 8-aminoquinoline drug class, primaquine can cause hemolytic anemia in individuals with G6PD deficiency (Hill et al., 2006).
PRIMAQUINE 309 Moreover, high-dose treatment can cause methemoglobinemia in dogs, rats, and primates (Lee et al., 1981). Primaquine is rapidly degraded in vivo (Fasinu et al., 2019), and there is fairly good evidence that its metabolites (e.g., PQ- 5,6-orthoquinone, 5-hydroxyprimaquine) can cause the generation of reactive oxygen species (in particular, hydrogen peroxide) in erythrocytes at physiologic concentrations (Bowman, 2005; Fasinu et al., 2019; VÃ¡zquez-Vivar and Augusto, 1992, 1994). Toxic doses of primaquine increase the circulating markers of liver damage in rabbits (El-Denshary, 1969) and reduce CYP450 levels in rats (Murray and Farrell, 1986). Primaquine at more physiologic concentrations bind to antioxidant species (GSH, N-acetyl cysteine) in liver microsomes (Garg et al., 2011). Coupled with primaquine-induced increases in reactive oxygen species in erythrocytes, the latter studies are consistent with primaquine causing a potentiation of oxidative stress, which can impair cellular function and viability. SYNTHESIS AND CONCLUSIONS Despite the fact that primaquine was first approved by FDA in 1952 for malaria prophylaxis, only four epidemiologic studies were identified that included some mention of adverse events or data collection that occurred â¥28 days post- cessation of primaquine that provided directly relevant information for assessing persistent or latent adverse events (Nasveld et al., 2010; Rueangweerayut et al., 2017; Schneiderman et al., 2018; Schwartz and Regev-Yochay, 1999). The studies are heterogeneous in the populations that were used (active military or veterans, travelers, and research volunteers); the modes of data collection on drug exposure, health outcomes, and covariates (administrative records, researcher collected, self-report); the type of prophylactic regimen and dosages used; and, particularly, the nature of the health outcomes that were considered. Furthermore, the relevant studies were notably inconsistent in the reporting of results, covering different time periods in relation to the cessation of the drug exposure and, in some cases, failing to provide information specifically for the time period of interest. Given the inherently imperfect information generated by any one study, it would be desirable to have similar studies to assess the consistency of the findings, but the diversity of the methods makes it very difficult to combine information across studies with confidence. The studies varied in methodologic quality and in the amount of usable infor- mation, so that their findings are not weighted equally in drawing conclusions. As described in Chapter 3, the committee considered several methodologic issues in assessing each studyâs contribution to the evidence base on persistent or latent health effects, including the overall study design, the quality of the 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
310 LONG-TERM HEALTH EFFECTS OF ANTIMALARIAL DRUGS was effectively isolated. Two studies were considered to contribute most to the evidence base (Schneiderman et al., 2018, and Nasveld et al., 2010), and to avoid repetition for multiple outcome categories, a short summary of each is presented first. The evidence summaries for outcome categories refer back to these short assessment summaries. For each health outcome category, the supporting information from FDA, known concurrent adverse events, case studies, information on selected subÂ populations, and experimental animal and in vitro studies is first summarized before 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 likelihood that problems may persist beyond the period after cessation of drug use. The synthesis of evidence is followed by a conclusion about the strength of evidence regarding an association between the use of primaquine and persistent or latent adverse events and whether the available evidence would support additional research into those outcomes. The outcomes are presented in the following order: neurologic disorders, psychiatric disorders, gastrointestinal disorders, eye disorders, cardio- vascular disorders, and other outcomes, including dermatologic and biochemical parameters. Epidemiologic Studies Presenting Contributory Evidence Schneiderman et al. (2018) conducted an analysis of self-reported health outcomes associated with the use of antimalarials in a population-based cohort of deployed and nondeployed U.S. veterans, using information collected as part of the NewGen Study. Exposure and outcomes were systematically obtained, and psychiatric outcomes were measured by standardized assessment instruments. The overall sample was large, and the researchers used a reasonably thorough set of covariates in models estimating the drugâoutcome associations. Although the time period of drug use and the timing of health outcomes were not directly addressed, given that the population was all veterans who had served between 2001 and 2008 and that the survey was not administered until 2009â2011, it is reasonable to assume that the antimalarial drug use had ceased some time before the study. The methodology and the low response rate (34% overall, of whom when weighted, 1.4% of deployed and 1.6% of nondeployed individuals used primaquine) may have led to the introduction of nonresponse, recall, or selection biases; however, the committee believes that the investigators used appropriate data analysis techniques to mitigate the effects of any biases that were present. Of the four included epidemiologic studies examining the persistent health effects of the use of primaquine for malaria prophylaxis, the committee weighted this study most heavily when generating its conclusions. Nasveld et al. (2010) conducted a randomized double-blind controlled study to compare the safety and tolerability of mefloquine followed by primaquine for
PRIMAQUINE 311 2 weeks (PART) with the safety and tolerability of tafenoquine for 26 weeks fol- lowed by placebo for 2 weeks in G6PD-normal Australian soldiers. A subset under- went extra safety assessments to investigate drug-induced phospholipidosis and methemoglobinemia as well as ophthalmic and cardiac safety. Drug compliance was observed and recorded for each subject using medication logs. In addition to the adverse-event assessments carried out while the soldiers were taking the drugs, there were additional assessments at 2 and 12 weeks following the completion of the regimen and telephone follow-ups at weeks 18 and 24. However, specific adverse events during the post-regimen phase were not detailed, except for the small safety subset that included only 21 primaquine users, all of whom had also taken mefloquine. Neurologic Disorders An examination of the associations of primaquine use with neurologic disor- ders does not indicate an increased risk for neurologic adverse events concurrent with primaquine use. Although dizziness was added to the FDA package insert in 2016 (FDA, 2016), there was no evidence from other sources of an association between primaquine and dizziness or any other concurrent, persistent, or latent neurologic outcome. A systematic review (Kolifarhood et al., 2017) found no significant differences in the incidence rate of concurrent neuropsychiatric adverse events between primaquine and placebo or between primaquine and other antiÂ alarials (mefloquine, doxycycline, or atovaquone/proguanil); fewer neuroÂ m psychiatric adverse events were reported with primaquine than with chloroquine in one study and than with tafenoquine in another. Three nonsystematic reviews found that neuropsychiatric symptoms have been reported rarely with primaquine use (Ashley et al., 2014; Castelli et al., 2010; Hill et al., 2006); however, the authors did not define the symptoms or outcomes that this neuropsychiatric cat- egory would encompass. Nasveld et al. (2002) reported more lethargy in women than in men who were administered a combination of doxycycline and primaquine; however, the relationship of these symptoms to primaquine could not be deter- mined because the two drugs were used together. Although animal studies indicate that very high doses of primaquine can induce cell loss in the brain, it is believed that such toxicity would not occur at the doses used for prophylaxis (Schmidt and Schmidt, 1951). None of the four epidemiologic studies that met the inclusion criteria specifi- cally examined neurologic outcomes following the cessation of primaquine. Based on the available evidence, the committee concludes that there is insuf- ficient or inadequate evidence of an association between the use of primaquine 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.
312 LONG-TERM HEALTH EFFECTS OF ANTIMALARIAL DRUGS Psychiatric Disorders An examination of the associations of primaquine use with psychiatric disor- ders does not indicate an increased risk for psychiatric adverse events with con- current primaquine use. There is no mention of adverse psychiatric events in the primaquine package insert (FDA, 2017a), and in a systematic review (Kolifarhood et al., 2017) no significant difference in the incidence rate of concurrent neuropsy- chiatric adverse events was observed between primaquine and placebo or between primaquine and other antimalarials (mefloquine, doxycycline, or atovaquone/ proguanil); fewer neuropsychiatric adverse events were reported with primaquine than with chloroquine in one study and than with tafenoquine in another. Three nonsystematic reviews noted that neuropsychiatric symptoms have been reported rarely with primaquine use (Ashley et al., 2014; Castelli et al., 2010; Hill et al., 2006); however, the authors did not define the symptoms or outcomes that the neuropsychiatric category would encompass. Although animal studies indicate that very high doses of primaquine can induce cell loss in the brain, it is believed that such toxicity would not occur at the doses used for prophylaxis (Schmidt and Schmidt, 1951). Schneiderman et al. (2018) examined mental health outcomes, including general mental health, PTSD, thoughts of death or self-harm, other anxiety, and major depression, among more than 19,400 veterans. However, only 133 of study participants used primaquine. After controlling for demographics, deployment status, and combat exposure, the use of primaquine alone was not associated with a composite mental health score, PTSD, thoughts of death or self-harm, or major depression when compared with nonusers of antimalarial drugs; however, other anxiety disorders were statistically significantly lower for primaquine users com- pared with nonusers of antimalarials drugs. In a subanalysis stratified by deploy- ment status, primaquine was associated with a statistically significantly decreased risk of anxiety in the deployed but no difference was observed in the nondeployed. Based on the available evidence, the committee concludes that there is insuf- ficient or inadequate evidence of an association between the use of primaquine for malaria prophylaxis and persistent or latent psychiatric events. Current evidence does not suggest further study of such an association is warranted, given the lack of evidence regarding biologic plausibility, adverse events associated with concur- rent use, or findings from the existing epidemiologic studies. Gastrointestinal Disorders The most common concurrent adverse event in primaquine users is minor gastrointestinal upset if the drug is taken on an empty stomach (Baird, 2019; Hill et al., 2006; Schlagenhauf et al., 2019). The risk of adverse gastrointestinal events increases with increasing doses of primaquine (Hill et al., 2006), and epi-
PRIMAQUINE 313 demiologic studies show that these events may include abdominal cramps, nausea, epigastric pain, vomiting, and diarrhea (Baird et al., 2001; Ebringer et al., 2011; Nasveld et al., 2002; Soto et al., 1998). The most recent package insert lists gastroÂ intestinal disorders in the general adverse reactions section but not in the warn- ings or precautions sections. In a systematic review (Kolifarhood et al., 2017), no difference in the incidence rate of concurrent adverse gastrointestinal events was observed between primaquine and placebo or between primaquine and other anti- malarials (mefloquine, doxycycline, or atovaquone/proguanil); in one study, fewer gastrointestinal adverse events were reported with primaquine than with chloro- quine, and in another study, fewer gastrointestinal adverse events were reported with primaquine than with tafenoquine. Nasveld et al. (2002) reported more nausea in women than in men who were administered a combination of doxycycline and primaquine; however, the relationship of these symptoms to primaquine could not be determined because the two drugs were used together. Experimental stud- ies suggest that primaquine can promote oxidative stress in cell culture, but it is unclear whether these actions are sufficient to impact gastrointestinal function in vivo. While primaquine exerts liver toxicity at high doses, it is unlikely to have adverse effects at doses used for malaria prophylaxis. None of the four epidemiologic studies that met the inclusion criteria specifi- cally examined gastrointestinal outcomes following the cessation of primaquine. Based on the available evidence, the committee concludes that there is insuf- ficient or inadequate evidence of an association between the use of primaquine 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, serious adverse events asso- ciated with concurrent use, or findings from the existing epidemiologic studies. Eye Disorders An examination of the associations of primaquine use with eye disorders does not indicate an increased risk for concurrent adverse events with primaquine use. Eye disorders are not mentioned in the primaquine package insert (FDA, 2017a), systematic and non-systematic reviews did not report on eye disorders, and experi- mental studies did not provide biologic plausibility for persistent or latent eye disorders. One case study suggested a possible link between primaquine-related hemolysis and persistent sequelae from central retinal vein occlusion. The Nasveld et al. (2010) study was designed to assess the ophthalmic safety of a regimen of mefloquine followed by primaquine in a subset of 21 soldiers. No adverse ophthalmic events were observed in that subset while taking mefloquine, so no ophthalmic follow-up was performed during or after primaquine use. The other three epidemiologic studies that met the committeeâs criteria for inclusion did not assess eye disorders.
314 LONG-TERM HEALTH EFFECTS OF ANTIMALARIAL DRUGS Based on the available evidence, the committee concludes that there is insuf- ficient or inadequate evidence of an association between the use of primaquine for malaria prophylaxis and persistent or latent eye disorders. Current evidence does not suggest further study of such an association is warranted, given the lack of evidence regarding biologic plausibility, adverse events associated with concur- rent use, or findings from the existing epidemiologic studies. Cardiovascular Disorders The FDA package insert was updated in 2015 to include the potential for cardiac QT interval prolongation (FDA, 2015). ECG monitoring is advised in patients with cardiac disease, long QT syndrome, a history of ventricular arrhyth- mias, uncorrected hypokalemia or hypomagnesemia, or bradycardia (<50 bpm) and who are taking concomitant administration of QT-interval-prolonging agents (FDA, 2017a). The systematic and non-systematic reviews did not report on cardioÂ ascular disorders. Experimental studies found that hypotension, cardiac v contractility, and arrhythmias had been observed with toxic doses of primaquine in rat and dog models. Cardiac effects can be linked to the blockade of sodium channels in cardioÂ yocytes, which results in decreased contractility (Orta-Salazar m et al., 2002). Primaquine also blocks the delayed rectifier hERG potassium chan- nels in HEK293 cells, effects that may be linked to the prolonged QT intervals or arrhythmias that occur in some individuals after taking antimalarials (Kim et al., 2010). Nasveld et al. (2010) assessed the cardiac safety of a regimen of mefloquine followed by primaquine in a subset of 21 soldiers. An increase in QT interval was reported in the mefloquine recipients, but no cardiac outcomes were observed at week 12 after cessation of primaquine. There is biologic plausibility for pri- maquine being associated with cardiac conduction problems. None of the other epidemiologic studies that met the inclusion criteria addressed the potential effects of prophylactic primaquine use and the outcomes of cardiovascular disorders. Based on the available evidence, the committee concludes that there is insuf- ficient or inadequate evidence of an association between the use of primaquine 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 Because the danger of hemolysis in G6PD-deficient persons is well charac- terized and because primaquine use is contraindicated in those with severe G6PD deficiency, the committee did not examine the evidence of adverse events associ- ated with G6PD deficiency in depth. Although the study was small and method-
PRIMAQUINE 315 ologically limited, Rueangweerayut et al. (2017) found three of five participants with moderate G6PD deficiency unable to tolerate 14 days of a prophylactic dose of primaquine. Although hemolysis does not persist once the drug is halted (Rishikesh and Saravu, 2016), untreated or uncontrolled hemolysis can result in arrhythmias, cardiomyopathy,Â heart failure, and death (Baird, 2019; NIH, n.d.), and released hemoglobin can cause damage to the kidney (Ashley et al., 2014), which may persist. Performing a G6PD-deficiency assessment before using prima- quine is a standard guideline; however, routine testing may misclassify patients, and hemolysis may occur in those who test G6PD normal, so it is suggested that hemoglobin be monitored upon initial primaquine exposure. A common occurrence in G6PD-normal and G6PD-deficient recipients is a mild, reversible methemoglobinemia (Baird, 2019; Hill et al., 2006; Rishikesh and Saravu, 2016). Persons who are deficient in the enzyme NADH methemoglobin reductase are very sensitive to primaquine (Hill et al., 2006), and their use of pri- maquine should be monitored for tolerance (FDA, 2017a). Methemoglobinemia can cause cyanosis, dizziness, or dyspnea (Hill et al., 2006; Schlagenhauf et al., 2019); more severe methemoglobinemia can lead to complications, including abnormal cardiac rhythms, altered mental status, delirium, seizures, coma, pro- found acidosis, and death (Denshaw-Burke et al., 2018). Nasveld et al. (2010) assessed methemoglobinemia levels in a subset of 21 G6PD-normal soldiers taking a regimen of mefloquine followed by primaquine. The mean methemoglobin levels increased by 0.1% in the participants taking mefloquine; the increases resolved by week 12 of follow-up after the cessation of primaquine. Although limited by its small sample size and the narrow range of measures examined, Rueangweerayut et al. (2017) also reported transient elevations of methemoglobin in both G6PD- normal and G6PD-deficient subjects, providing weak supportive evidence. Rare serious outcomes including death have been attributed to primaquine- associated hemolysis; however, the committee found no controlled studies docu- menting persistent or latent events associated with hemolysis or methemoglobin- emia resulting from prophylactic doses of primaquine. REFERENCES 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 42:1103-1114. Alving, A. S., C. F. Johnson, A. R. Tarlov, G. J. Brewer, R. W. Kellermeyer, and P. E. Carson. 1960. Mitigation of the haemolytic effect of primaquine and enhancement of its action against exo- erythrocytic forms of the Chesson strain of Plasmodium vivax by intermittent regimens of drug administration: A preliminary report. Bull WHO 22:621-631. Ashley, E. A., J. Recht, and N. J. White. 2014. Primaquine: The risks and the benefits. Malar J 13:418.
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