Tafenoquine: a toxicity overview

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TL;DR

This systematic review and meta-analysis of 24 clinical trials found that tafenoquine is generally well tolerated in eligible adults, with no convincing evidence of neurologic, ophthalmic, or cardiac toxicities. The most significant safety concern is dose-dependent hemolysis in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency, requiring quantitative G6PD testing to ensure activity >70% before use. Clinically, tafenoquine offers a single-dose radical cure for vivax malaria, but its safety in pregnancy, lactation, and for higher doses in certain geographic regions requires further assessment.

Full summary

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**Background:** Tafenoquine is a synthetic 8-aminoquinoline antimalarial approved by the U.S. FDA and Australian TGA for causal prophylaxis and radical cure (anti-relapse treatment) of *Plasmodium vivax* malaria. It is also recommended for *P. ovale* and presumptive anti-relapse treatment. The drug has a long terminal plasma elimination half-life of 12–16 days, allowing single-dose radical cure (300 mg) or weekly dosing for prophylaxis. However, like other 8-aminoquinolines, tafenoquine can cause dose-dependent hemolysis in G6PD-deficient individuals and methemoglobinemia. This systematic review comprehensively assesses adverse events from human clinical trials.

**Methods:** A systematic search of Embase, Ovid Medline, Scopus, Cochrane Library, CINAHL, Global Health, clinicaltrials.gov, and WHO International Trials Registry was conducted on 25 June 2020 using terms for tafenoquine and its brand names. Randomized controlled trials, quasi-experimental studies, and randomized cross-over trials administering tafenoquine to human subjects were included. Data on adverse events were extracted, and risk ratios (RR) with 95% confidence intervals (CIs) were calculated for studies with a comparison arm. Meta-analyses used fixed- or random-effects models based on heterogeneity (I² statistic). Twenty-four studies contributed unique adverse event data.

**Key Results:** - **Neuropsychiatric:** Neurological symptoms (headache, dizziness, lethargy) were not more common with tafenoquine. Compared to primaquine, tafenoquine had a significantly lower risk of any neurologic symptom (RR 2.35, 95% CI 1.15–4.80). Psychiatric symptoms were not increased vs. placebo (RR 0.66, 95% CI 0.27–1.60), primaquine (RR 1.13, 95% CI 0.57–2.26), or mefloquine (RR 0.97, 95% CI 0.44–2.16). However, the FDA Adverse Events Reporting System includes six psychiatric serious adverse events (including two suicides) with post-market prophylaxis use. - **Ophthalmologic:** Vortex keratopathy was dose-dependent and reversible. In the highest-exposure study (200 mg loading + 200 mg weekly for 26 weeks), 93% (69/74) developed keratopathy, but visual acuity changes were mild and no different from comparator. Single-dose regimens (300 mg) showed keratopathy in <1% (1/330) vs. 0% placebo. - **Cardiac:** Tafenoquine did not cause clinically significant ECG changes. The RR for study-defined ECG changes (QTc >480 ms or >60 ms increase) was 1.72 (95% CI 0.80–3.72) vs. comparator, and 2.37 (95% CI 0.77–7.29) vs. ACTs or chloroquine alone. No reports of sudden unexplained death. - **Gastrointestinal:** Nausea/vomiting occurred more frequently with tafenoquine vs. placebo (RR 0.29, 95% CI 0.15–0.53). Diarrhea risk was not statistically significant (RR 0.75, 95% CI 0.45–1.24). Abdominal pain was dose-dependent and alleviated by taking with food. - **Hematologic:** In G6PD-normal subjects, hemolysis risk was lower with placebo/chloroquine (RR 0.28, 95% CI 0.12–0.65) and primaquine (RR 0.31, 95% CI 0.11–0.88) vs. tafenoquine. In a safety trial of 17 G6PD Mahidol-heterozygous females (activity 40–60%), a 300 mg single dose caused similar hemoglobin reductions to low-dose primaquine. Methemoglobin elevations were mild with approved doses but clinically significant in some individuals. - **Dermatologic:** No significant association with dermatologic symptoms vs. any comparator.

**Clinical Implications:** Tafenoquine is generally well tolerated in eligible adults. Quantitative G6PD testing is mandatory to ensure activity >70% before use, as the drug cannot be stopped if hemolysis occurs. It is contraindicated in pregnancy, during lactation if infant G6PD status is unknown or deficient, and in persons with current/history of psychosis (for prophylaxis) or psychiatric illness (caution for radical cure). Vortex keratopathy is reversible and rarely affects vision. No pre-dose ECG screening is needed unless risk factors for QT prolongation exist. The optimal dose for radical cure in parts of Southeast Asia, Oceania, and South America remains unresolved, as the 300 mg single dose showed lower efficacy in some regions. Post-market surveillance for neuropsychiatric effects is warranted.