TABLE 2. Summary of key adverse events observed in persons receiving tafenoquine at recommended doses versus placebo or mefloquine.
| Year published | Study length | Drug regimen | Sample Size | Adverse event type reported, no. (%) |
|||||
|---|---|---|---|---|---|---|---|---|---|
| Gastrointestinal | Dermatologic | Neurologic | Ophthalmologic | Cardiac | Hematologic | ||||
|
Prophylaxis dose
| |||||||||
| 2001* |
13 weeks intervention, follow up 4 wks |
TQ 200 mg x 3 days, then weekly |
55 |
Gastrointestinal 16 (29) |
Any dermatologic 12 (22) |
Neurologic 14 (26) |
— |
— |
Methemoglobinemia, mean plateau concentrations 2.5%±1.6% |
| -Abdominal pain 2 (4) |
-Skin disorder 6 (11) |
-Headache 13 (24) |
|||||||
| -Constipation 4 (7) |
-Rash 2 (4) |
||||||||
| -Diarrhea 4 (7 | |||||||||
| -Gastritis 2(4) | |||||||||
| -Gastroenteritis 3(6) | |||||||||
| TQ 200 mg x 3 days |
60 |
Gastrointestinal 20 (33) |
Any dermatologic 12 (20) |
Neurologic 11 (18) |
— |
— |
— |
||
| -Abdominal pain 1 (2) |
-Skin disorder 5 (8) |
-Headache 10 (17) |
|||||||
| -Constipation 7 (12) |
-Rash 1 (2) |
||||||||
| -Diarrhea 4 (7) | |||||||||
| -Gastritis 4 (7) | |||||||||
| -Gastroenteritis 7 (12) | |||||||||
| Placebo |
61 |
Gastrointestinal 17 (28) |
Any dermatologic 6 (8) |
Neurologic 11 (18) |
— |
— |
— |
||
| -Abdominal pain 2 (3) |
-Skin disorder 4 (7) |
-Headache 11 (18) |
|||||||
| -Constipation 3 (5) |
-Rash 1 (2) |
||||||||
| -Diarrhea 2 (3) | |||||||||
| -Gastritis 4 (7) | |||||||||
| -Gastroenteritis 5 (8) | |||||||||
| 2003† |
12 weeks intervention, 4 wks additional follow-up |
TQ 200 mg x 3 days, then weekly |
91 |
Elevated ALT 6 (6) § |
— |
— |
— |
— |
— |
| Gastritis 5 (5) | |||||||||
| MQ 250 mg/week |
46 |
Elevated ALT 0 |
— |
— |
— |
— |
— |
||
| Gastritis 1 (3) | |||||||||
| Placebo |
94 |
Elevated ALT 2 (2) |
— |
— |
— |
— |
— |
||
| Gastritis 2 (2) | |||||||||
| 2010¶ |
6 mos intervention, follow-up 20 wks |
TQ 200 mg x 3 days, then weekly |
492 |
Severe gastrointestinal 8 (1) ** |
— |
Neuropsychiatric 64 (13)†† |
Vortex keratopathy 69/74 (93) §§ |
— |
Methemoglobinemia, mean increase 1.8% |
| MQ 250 mg/week |
162 |
Severe gastrointestinal 0 (0) |
— |
Neuropsychiatric 23 (14) |
Vortex keratopathy 0 (0) |
— |
Methemoglobinemia, mean increase 0.1% |
||
| 2018 ¶¶ |
34 days after initiation of TQ (challenge study) |
TQ 200mg x 3 days and then 200 mg on day 10 |
12 |
Abdominal discomfort 1 (8) |
— |
Headache 4 (33) |
— |
— |
Hemoglobin decreased 2 (17) |
| Abdominal pain 1 (8) |
Hypoesthesia 0 (0) |
||||||||
| Diarrhea 0 (0) |
Lethargy 0 (0) |
||||||||
| Dry mouth 1 (8) | |||||||||
| Nausea 1 (8) | |||||||||
| Vomiting 1 (8) | |||||||||
| Placebo |
4 |
Abdominal discomfort 1 (25) |
— |
Headache 4 (100) |
— |
— |
Hemoglobin decreased 0 (0) |
||
| Abdominal pain 0 (0) |
Hypoesthesia 1 (25) |
||||||||
| Diarrhea 1 (25) |
Lethargy 1 (25) |
||||||||
| Dry mouth 0 (0) | |||||||||
| Nausea 3 (75) | |||||||||
| Vomiting 2 (50) | |||||||||
|
Antirelapse therapy dose
| |||||||||
| 2014*** |
Follow up to 180 days posttreatment |
TQ 300 mg plus CQ |
57 |
Upper abdominal pain 6 (11) |
Pruritus 8 (14) |
Asthenia 5 (9) |
— |
QT prolongation 3 (5) |
Anemia 1 (2) |
| Nausea 5 (9) |
Insomnia 5 (9) |
||||||||
| PQ 15 mg plus CQ |
50 |
Upper abdominal pain 7 (14) |
Pruritus 3 (6) |
Asthenia 0 (0) |
— |
QT prolongation 5 (10) |
Anemia 0 (0) |
||
| Nausea 4 (8) |
Insomnia 3 (6) |
||||||||
| CQ only |
54 |
Upper abdominal pain 5 (9) |
Pruritus 7 (13) |
Asthenia 0 (0) |
— |
QT prolongation 4 (7) |
Anemia 0 (0) |
||
| Nausea 3 (6) |
Insomnia 1 (2) |
||||||||
| 2019††† |
Follow up to 180 days posttreatment |
TQ 300 mg plus CQ |
166 |
Nausea 16 (10) |
Pruritus 20 (12) |
Dizziness 27 (16) |
Vortex keratopathy 1 (1) |
— |
— |
| Vomiting 11 (7) |
Headache 19 (11) |
Retinal hypo-pigmentation 1 (1) |
|||||||
| Retinal hyper-pigmentation 1 (1) | |||||||||
| PQ 15 mg plus CQ |
85 |
Nausea 6 (7) |
Pruritus 19 (22) |
Dizziness 13 (15) |
Retinal hypo-pigmentation 1 (2) |
— |
— |
||
| Vomiting 5 (6) |
Headache 10 (12) |
||||||||
| 2019 §§§ | Follow up to 180 days posttreatment | TQ 300 mg plus CQ |
260 |
Nausea 16 (6) |
Pruritus 127 (49) |
Dizziness 22 (9) |
Unilateral keratopathy 1 |
— |
Hemoglobin decreased >3g/dL 14 (5) |
| Vomiting 15 (6) |
Headache 12 (5) |
Unilateral retinal change 2 |
|||||||
| Diarrhea 10 (4) | |||||||||
| Upper abdominal pain 8 (3) | |||||||||
| Elevated ALT 6 (2) | |||||||||
| PQ 15 mg plus CQ |
129 |
Nausea 7 (5) |
Pruritus 14 (11) |
Dizziness 8 (6) |
Retinal hypo-pigmentation 1 |
— |
Hemoglobin decreased >3g/dL 2 (2) |
||
| Vomiting 9 (7) |
Headache 5 (4) |
||||||||
| Diarrhea 2 (2) | |||||||||
| Upper abdominal pain 6 (5) | |||||||||
| Elevated ALT 3 (2) | |||||||||
| CQ only | 133 | Nausea 9 (7) |
Pruritus 17 (13) | Dizziness 4 (3) |
— | — | Hemoglobin decreased >3g/dL 2 (2) | ||
| Vomiting 7 (5) |
Headache 9 (7) | ||||||||
| Diarrhea 4 (3) | |||||||||
| Upper abdominal pain 9 (7) | |||||||||
| Elevated ALT 6 (5) | |||||||||
Abbreviations: ALT = alanine aminotransferase; CQ = chloroquine; MQ = mefloquine; PQ = primaquine; TQ = tafenoquine.
* Shanks GD, Oloo AJ, Aleman GM, et al. A new primaquine analog, tafenoquine (WR 238605), for prophylaxis against Plasmodium falciparum malaria. Clin Infect Dis 2001;33:1968–74.
† Hale BR, Owusu-Agyei S, Fryauff DJ, et al. A randomized, double-blind, placebo-controlled, dose-ranging trial of tafenoquine for weekly prophylaxis against Plasmodium falciparum. Clin Infect Dis 2003;36:541–9.
§ For all six, ALT exceeded a predetermined threshold and returned to normal levels when drug was discontinued. No clinical significance.
¶ Nasveld PE, Edstein MD, Reid M, et al. Randomized, double-blind study of the safety, tolerability, and efficacy of tafenoquine versus mefloquine for malaria prophylaxis in nonimmune subjects. Antimicrob Agents Chemother 2010;54:792–8.
** Most common gastrointestinal events: abdominal pain, constipation, and diarrhea. No difference between tafenoquine and mefloquine gastrointestinal events.
†† No difference between tafenoquine and mefloquine, and no severe neuropsychiatric events observed. Most common events were vertigo, dizziness, and sleep disorders. One tafenoquine subject withdrew because of depression (moderate), and one for hyperesthesia (moderate).
§§ Subset analysis for vortex keratopathy. Not associated with visual disturbances and resolved by 1 year.
¶¶ McCarthy JS, Smith B, Reid M, et al. Blood schizonticidal activity and safety of tafenoquine when administered as chemoprophylaxis to healthy, non-immune participants followed by blood stage Plasmodium falciparum challenge: a randomized, double-blinded, placebo-controlled Phase 1b study. Clin Infect Dis 2019;69:480–6.
*** Llanos-Cuentas A, Lacerda MV, Rueangweerayut R, Krudsood S, Gupta SK, Kochar SK, et al. Tafenoquine plus chloroquine for the treatment and relapse prevention of Plasmodium vivax malaria (DETECTIVE): a multicentre, double-blind, randomized, phase 2b dose-selection study. Lancet. 2014;383:1049–58.
††† Llanos-Cuentas A, Lacerda MVG, Hien TT, et al. Tafenoquine versus primaquine to prevent relapse of Plasmodium vivax malaria (GATHER). N Engl J Med 2019;380:229–41.
§§§ Lacerda MVG, Llanos-Cuentas A, Krudsood S, et al. Single-dose tafenoquine to prevent relapse of Plasmodium vivax malaria (DETECTIVE Phase III). N Engl J Med 2019;380:215–28.