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5 Tafenoquine
Pages 177-216

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From page 177...
... of Plasmodium vivax malaria in people receiving therapy for acute P vivax infection (FDA, 2018a)
From page 178...
... 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 committee's inclusion criteria regarding the timing of follow-up, followed 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.
From page 179...
... 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)
From page 180...
... 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." The package insert notes that psychiatric adverse reactions in participants receiving tafenoquine in clinical trials included sleep disturbances (2.5%) , depression/depressed mood (0.3%)
From page 181...
... . 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)
From page 182...
... Defense Health Agency document outlines policy for the force health protection use of tafenoquine for malaria prophylaxis in U.S. service members (DoD, 2019)
From page 183...
... . It heard or reviewed submitted testimony from government agencies (Department of Defence, Department of Health, Department of Veterans' Affairs, Australian Defence Force Malaria and Infectious Disease Institute, Indo-Pacific Centre for Health Security, Department of Foreign Affairs and Trade Repatriation Medical Authority)
From page 184...
... 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.
From page 185...
... FDA Briefing Document Data from five clinical trials in which tafenoquine recipients received FDAapproved prophylactic loading and maintenance dosages are presented both in the FDA package insert and in the FDA briefing document (FDA, 2018c,d)
From page 186...
... . In the safety set, psychiatric adverse reactions were reported in 3.9% (32/825)
From page 187...
... 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 ≥1% (FDA, 2018c)
From page 188...
... . 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%)
From page 189...
... 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 committee's inclusion criteria, as defined in Chapter 3.
From page 190...
... 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 persistent or latent adverse events. The study reported persistent vortex keratopathy that resolved by 1 year and had no effect on vision.
From page 191...
... 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.
From page 192...
... 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.
From page 193...
... Safety was evaluated by physical examination, vital signs, clinical laboratory tests (hematology, biochemistry, and urinalysis) and adverse event monitoring.
From page 194...
... , 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.
From page 195...
... A design limitation for the committee's purposes 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)
From page 196...
... . 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 methemoglobin percentage above the reference range at screening; or a history of retinal eye surgery, Lasik surgery within 90 days, or retinal or corneal abnormalities.
From page 197...
... Clinical laboratory values and vital signs, methemoglobin levels, and ophthalmic measures were evaluated 1 and 2 months post-drug-cessation. Beyond these few specific assessments, 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.
From page 198...
... 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)
From page 199...
... 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%)
From page 200...
... 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)
From page 201...
... 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.
From page 202...
... 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.
From page 203...
... 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 studies' 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 summarized, after which the evidence from the post-cessation epidemiologic studies is described.
From page 204...
... 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 studies. The FDA package insert and the FDA briefing document both referred to a safety set of data comprising five studies (FDA, 2018c,d)
From page 205...
... The FDA package insert and the FDA briefing document both referred to a safety set of data comprising five studies (FDA, 2018c,d)
From page 206...
... Based on the available evidence, the committee concludes that there is insufficient 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.
From page 207...
... 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 21–93% of tafenoquine recipients in three trials that included ophthalmic evaluations (Leary et al., 2009; Nasveld et al., 2010; a malaria-treatment trial [NCT #0129060]
From page 208...
... Current evidence suggests further study of such an association is warranted, given evidence regarding biologic plausibility, adverse events associated with concurrent 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)
From page 209...
... 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 ≥1% of tafenoquine recipients (FDA, 2018d)
From page 210...
... . Referring to a safety set of five clinical trials, the package insert reports that asymptomatic elevations in methemoglobin occurred in 13% of tafenoquine recipients.
From page 211...
... . Five epidemiologic studies that met the inclusion criteria included data for hematologic adverse events for which the timing post-drug-cessation was specified.
From page 212...
... Am J Trop Med Hyg 58:645-649.
From page 213...
... 2007. Gender differences in gastrointestinal disturbances and plasma concentrations of tafeno quine in healthy volunteers after tafenoquine administration for post-exposure vivax malaria prophylaxis.
From page 214...
... 2019. Tafenoquine versus primaquine to prevent relapse of Plasmodium vivax malaria.
From page 215...
... 2016. Primaquine treatment and relapse in Plasmodium vivax malaria.
From page 216...
... 2004. Efficacy of monthly tafenoquine for prophylaxis of Plasmodium vivax and multidrug-resistant P


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