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8 Primaquine
Pages 291-322

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From page 291...
... . 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
From page 292...
... . The dosage and administration information in the primaquine FDA package insert notes further that primaquine is recommended "following the termination of chloroquine phosphate suppressive therapy in an area where vivax malaria is endemic" (FDA, 2017a)
From page 293...
... 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 committee's 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 summarized.
From page 294...
... . 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.
From page 295...
... 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.
From page 296...
... , DoD, August 22, 2019. 3  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)
From page 297...
... For instance, a 2003 issuance stated that terminal malaria prophylaxis "is no longer required" in Iraq (DoD, 2003b) , presumably because intelligence had determined that control over malaria had been regained.
From page 298...
... . 5-Hydroxyprimaquine, formed by CYP450, primarily the CYP2D6 isoform 5  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)
From page 299...
... 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-primaquinecessation are then summarized by population category (military or veterans, travelers, and research volunteers)
From page 300...
... 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)
From page 301...
... (2018) conducted a retrospective observational analysis of self-reported health outcomes associated with the use of antimalarial drugs in a cohort of U.S.
From page 302...
... Because it is not clear how many people in the mefloquine-plus group may have also used primaquine, the results of that group are not included in the committee's 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 component scores below the U.S.
From page 303...
... was statistically significantly lower -- an indication of better physical health -- for primaquine users compared with non­ 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 0.06–0.67)
From page 304...
... Adverse-event monitoring was supplemented by a review of the subjects' 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)
From page 305...
... 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
From page 306...
... . The study was limited by its small sample size and by the narrow range of measures it examined. In addition, although the final follow-up visit at day 56 met the inclusion criteria of ≥28 days following drug cessation, there was no information reported from that visit.
From page 307...
... 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.
From page 308...
... . Primaquine also blocks the delayed rectifier hERG potassium channels 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)
From page 309...
... 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 ≥28 days postcessation 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)
From page 310...
... 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, cardiovascular disorders, and other outcomes, including dermatologic and biochemical parameters.
From page 311...
... Based on the available evidence, the committee concludes that there is insufficient 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 concurrent use, or findings from the existing epidemiologic studies.
From page 312...
... 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. 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)
From page 313...
... Current evidence does not suggest further study of such an association is warranted, given the lack of evidence regarding biologic plausibility, serious adverse events associated 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.
From page 314...
... 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 insufficient or inadequate evidence of an association between the use of primaquine for malaria prophylaxis and persistent or latent cardiovascular events.
From page 315...
... Rare serious outcomes including death have been attributed to primaquineassociated hemolysis; however, the committee found no controlled studies documenting persistent or latent events associated with hemolysis or methemoglobinemia resulting from prophylactic doses of primaquine. REFERENCES Ackert, J., K
From page 316...
... 2004. Toxicity of commonly-used antimalarial drugs.
From page 317...
... Provided by 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) , DoD, December 19, 2019.
From page 318...
... Trans R Soc Trop Med Hyg 105(10)
From page 319...
... 2006. Role of U.S. military research programs in the development of U.S. Food and Drug Administration-approved antimalarial drugs.
From page 320...
... Am J Trop Med Hyg 99(3)
From page 321...
... 1992. Hydroxylated metabolites of the antimalarial drug prima quine.


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