Tafenoquine: a toxicity overview

ABSTRACT

Introduction: A century-long history in 8-aminoquinolines, the only anti-malaria drug class preventing malaria relapse, has resulted in the approval of tafenoquine by the U.S. Food and Drug Administration (FDA) and the Australian Therapeutic Goods Administration (TGA) and to date registration in Brazil and Thailand. Tafenoquine is an alternative anti-relapse treatment for vivax malaria and malaria prophylaxis. It should not be given in pregnancy, during lactation of infants with glucose-6-phosphate dehydrogenase (G6PD) unknown or deficient status, and in those with G6PD deficiency or psychiatric illness.

Areas covered: This systematic review assesses tafenoquine associated adverse events in English-language, human clinical trials. Meta-analysis of commonly reported adverse events was conducted and grouped by comparison arms.Expert opinion: Tafenoquine, either for radical cure or prophylaxis, is generally well tolerated in adults. There is no convincing evidence for neurologic, ophthalmic, and cardiac toxicities. Psychotic disorder which has been attributed to higher doses is a contraindication for the chemoprophylaxis indication and psychiatric illness is a warning for the radical cure indication. Pregnancy assessment and quantitative G6PD testing are required. The optimal radical curative regimen including the tafenoquine dose along with its safety for parts of Southeast Asia, South America, and Oceania needs further assessment.

KEYWORDS:

• 8-aminoquinoline
• adverse effect
• causal prophylaxis
• chemoprophylaxis
• radical cure
• meta-analysis
• plasmodium vivax
• relapse prevention
• drug safety
• tafenoquine

Article highlights

• Tafenoquine is a newly registered 8-aminoquinoline that is active against all stages of malaria. It can be used for causal prophylaxis or radical cure of Plasmodium vivax. There is no regulatory approval for the transmission-blocking, blood-stage treatment of any malaria, or presumptive anti-relapse treatment (PART) indications. However, the U.S. Centers for Disease Control and Prevention (CDC) malaria guidance has extended the use of tafenoquine for the radical cure to P. ovale and PART (Haston et al., 2019 [4]).

• Tafenoquine has a side effect profile similar to primaquine, which means generally it is well tolerated. However, 8-aminoquinolines including tafenoquine cause hemolysis in persons with intermediate and deficient G6PD activity. Psychosis is listed as a contraindication in the two approved tafenoquine labels (the U.S. Food and Drug Administration (FDA) and the Australian Therapeutic Goods Administration (TGA)) for causal prophylaxis while a history or current symptoms of psychiatric illness are a precaution in the radical cure labels with the same stringent regulatory agencies. Other less commonly known adverse effects have been reported.

• Twenty-four clinical trials reporting adverse events data comparing tafenoquine to a comparator drug or placebo arm were included in this systematic review.

• In the meta-analyses, no differences between tafenoquine and comparator groups were seen for neuropsychiatric, dermatologic, and most gastrointestinal adverse effects.

• In the five studies that assessed ophthalmologic outcomes, the clinical effects were mild and no different from the comparator.

• Tafenoquine monotherapy does not prolong the corrected QT interval.

• Precise comparisons of hemolysis were not possible due to methodologic heterogeneity. Although the comparison arm was favored, large hemoglobin reductions were not observed in G6PD-normal participants after tafenoquine use.

• Meta-analysis could not be performed for methemoglobin due to heterogenous reporting of results. Mild methemoglobin elevations were common. Clinically significant elevations were observed; however, they were uncommon.

• Pregnancy assessment and quantitative G6PD testing in the patient and breastfed infant, if applicable, are necessary before tafenoquine administration.

• Symptoms occurring up to 3 months after the last dose might be tafenoquine related due to its long plasma elimination half-life (12-17 days).

• In parts of South America, SE Asia, and Oceania, the radical curative efficacy of tafenoquine is low; in some areas both tafenoquine and low-dose primaquine have low efficacy. Further studies in these areas are needed to optimize the radical curative 8-aminoquinoline doses and select viable schizonticidal partner drugs and regimens for the anti-relapse treatment of P. vivax malaria. Continued safety assessments are needed to monitor tafenoquine toxicity. Although this should be balanced with the benefit of preventing morbidity from repeated P. vivax infections (e.g. anemia, hospitalization, low birth weight) and decreasing malaria transmission when efficacious tafenoquine regimens are used.

This box summarizes key points contained in the article.

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Acknowledgments

Many thanks to Professor G. Dennis Shanks (Director Australian Defence Force Malaria and Infectious Disease Institute) and Dr. Mark Fukuda (Scientific Director, DoD Defense Malaria Assistance Program, AFRIMS) for sharing their experience and insight on tafenoquine; to Dr. Germana Bancone for sharing her expertise in G6PD deficiency; and to Professor Sir Nicholas J White (Mahidol Oxford Tropical Medicine Research Unit, Thailand) and Professor François H Nosten (Shoklo Malaria Research Unit, Thailand) for their valuable guidance on the final drafts of this paper.

Declaration of interest

J Hwang receives salary from the U.S. President’s Malaria Initiative. CS Chu is supported by the Wellcome Trust [grant number 089179/Z/09/Z]. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

The findings and conclusions in this report are those of the author(s) and do not necessarily represent the official position of the Centers for Disease Control and Prevention. Reference to specific commercial products, manufacturers, companies, or trademarks does not constitute its endorsement or recommendation by the U.S. Government, Department of Health and Human Services, or Centers for Disease Control and Prevention.

Reviewer disclosures

A reviewer on this manuscript has disclosed that they are a full-time employee at MMV and they have developed tafenoquine in partnership with GSK for the radical cure indication. Another reviewer on this manuscript has disclosed that they are an employee of MMV and has been part of the Tafenoquine project team until the end of the phase IIb DETECTIVE study (Detective I). All other peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Supplementary material

Supplemental data for this article can be accessed here.

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Funding

This paper was not funded.