Tafenoquine for Malaria Disclosure: Prophylaxis and Antirelapse - PDF document

Tafenoquine for Malaria Disclosure: Prophylaxis and Antirelapse Therapy Co-investigator on postmarketing surveillance for adverse events of tafenoquine (Krintafel) labeled for antirelapse therapy in the U.S. No financial disclosures Kathrine R. Tan MD, MPH CISTM June 6, 2019 Center for Global Health Division of Parasitic Diseases and Malaria Plasmodium Life Cycle (Abridged) P. vivax — Widest Geographic Distribution of the Human Malarias <1 month later >1 month later ( P. vivax, P. ovale ) Gething 2012 Most Antimalarials Don’t Kill Hypnozoites P. vivax can cause severe disease and death Atovaquone-proguanil � In 2016 in the U.S. � 5% severe malaria cases � 2/7 deaths � Among U.S. cases 1985–2011 � Odds of death severe falciparum vs severe vivax similar (Hwang 2014) Artemisinins Primaquine Chloroquine Doxycycline Mefloquine Quinine

Hypnozoites and Malaria Prophylaxis Hypnozoites and Malaria Prophylaxis Atovaquone-proguanil Chloroquine Doxycycline Mefloquine Weeks after departure Weeks after departure 4 4 0 1 0 1 (AP) P. falciparum P. falciparum P. vivax P. vivax P. ovale P. ovale Hypnozoites and Malaria Prophylaxis Hypnozoites and Treatment of P. vivax and P. ovale Atovaquone-proguanil Chloroquine Doxycycline Schizontozide Hypnozoitocide Mefloquine (until recently, only option Weeks after departure primaquine x 14 days) 4 0 1 (AP) P. falciparum P. vivax P. ovale Primaquine (off label) Lengthy Regimen May Challenge Adherence 8-aminoquinolines Development to Approval Prophylaxis Atovaquone-proguanil Chloroquine Doxycycline Mefloquine Weeks after departure 4 0 1 In the U.S.: Primaquine Arakoda — Prophylaxis developed and Tafenoquine developed Krintafel — Antirelapse therapy approved and approved Treatment ( P. vivax, P. ovale ) Chloroquine 1940 1950 1960 1970 2020 1980 1990 2000 2010 Primaquine World Korean Vietnam War War War II Day of treatment 0 1 2 3 15

8-aminoquinolines Prophylaxis: What Dose? Half-lives (Semi-immune Adults) Regimen (n) Protective efficacy (95% CI) Placebo (59) Ref. Primaquine TQ 400 mg x 3 days, then placebo weekly (54) 68% (53–79%) Half-life: 6 Tafenoquine TQ 200 mg x 3 days, then 200 mg weekly (53) 86% (73–93%) Half-life: hours 15 days TQ 400 mg x 3 days, then 400 mg weekly (57) 89% (77–95%) Shanks CID 2001 Prophylaxis: Efficacy Tafenoquine vs Mefloquine Prophylaxis: Minimum Maintenance Dose (Non-immune Adults) (Semi-immune Adults) Prophylactic outcome during the study (50 weeks) TQ (N=492) MQ (N=162) Regimen (n) Protective efficacy (95% CI) Success 468 (95.1%) 156 (96.3%) Placebo (94) Ref. Failure ( P. vivax ) 4 (0.8%) 1 (0.6%) MQ 250 mg weekly (46) 86% (72-93%) Missing 20 (4.1%) 5 (3.1%) TQ 25 mg x 3 days, then 25 mg/wk (93) 32% (20–43%) TQ 50 mg x 3 days, then 50 mg/wk (91)) 84% (75–91%) Difference in success proportion (TQ-MQ) [95%CI]: -1.2% [-4.7%, 2.3%] TQ 100 mg x 3 days, then 100 mg/wk (94) 87% (78–93%) TQ 200 mg x 3 days, then 200 mg/wk (91) 86% (76–92%) Hale CID 2003 Nasveld Antimicrob Agents Chemother 2010 Table from FDA analysis (intention to treat) Antirelapse Therapy: What Dose? Prophylaxis: Activity Against P. falciparum Schizonts DETECTIVE Part 1 Relapse free at 6 months TQ 600 mg 92% (80 –– 97) TQ 300 mg 89% (77 – 95) PQ 15mgx14d 77% (63 –– 87) T T T T Day Placebo 38% (23 –– 52) 1 2 3 10 13 32 P P P P McCarthy CID 2018 Llanos-Cuentas Lancet 2014

Antirelapse Therapy: Efficacy of Tafenoquine vs Placebo Antirelapse Therapy: Efficacy of Tafenoquine vs Primaquine DETECTIVE Part 2 GATHER Meta-Analysis Relapse free at 6 months Primaquine 73% (66 – 79) Tafenoquine 67% (61 – 72) Lacerda NEJM 2019 Llanos-Cuentas NEJM 2019 Hemolytic Anemia and Hemolytic Anemia and Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency G6PD Activity G6PD Activity X Y X Y X Y X Y + O + O - O X X - O X X + - + - X X X X X X X X - - - - + + + + Missed by qualitative tests Intermediate Normal Intermediate Normal Deficient Deficient Adverse Events at Prophylactic Doses* Psychiatric Adverse Events* N=825 (Prophylactic Doses) � Adverse events in >2% � Observed in 4% � GI: Diarrhea, nausea, vomiting � Most common: Insomnia (1.2%), weird dreams (0.6%), anxiety (0.2%) � Neuro: Headache, dizziness � Other adverse events (all with prior history): � Psychiatric adverse events � Depression/depressed mood (3 cases) � Not of clinical significance: Methemoglobinemia, vortex keratopathy � Attempted suicide (1 case) � Adverse events in <2% but of interest � Hypersensitivity reactions *U.S. Food and Drug Administration (FDA) safety review and report *FDA safety review and report

Adverse Events at Antirelapse Therapy Dose Adverse Reactions on Labels (N=483) � Adverse events >2% � Delayed presentation possible — long half-life � GI: Diarrhea, nausea vomiting � GI: Diarrhea, nausea, vomiting, increased liver enzymes � Neuro: Headache, dizziness � Neuro: Headache, dizziness � Psychiatric adverse events � Heme: Decreased hemoglobin � Not of clinical significance: Methemoglobinemia � Musculoskeletal: Back pain � Psychiatric adverse events 3% � Insomnia � Psych: Insomnia, abnormal dreams, anxiety, depression � Anxiety <1% � No severe events *FDA safety review and report Contraindications and Warnings Tafenoquine in Practice � Consider criteria: � G6PD deficiency � Adult ( ≥ 16 years old for antirelapse therapy) � Pregnant women (unknown status fetus) � Not pregnant � Breastfeeding women (if infant status unknown, or deficient) � Not breastfeeding (or if breastfeeding infant with normal G6PD) � History of psychiatric illness � No history of psychiatric illness � Known hypersensitivity � No known hypersensitivity to 8-aminoquinolines � Do quantitative G6PD testing � If normal quantitative G6PD test – OK to give Short-Term (<6 months) Prophylaxis Antirelapse Therapy for P. vivax Malaria* in ≥ 16 year olds All Species of Malaria in Adults (Krintafel in U.S.) (Arakoda in U.S.) = 150 mg = 100 mg Chloroquine Tafenoquine Week Day of treatment Travel 3 0 1 Travel 2 Post-travel 0 2 3 -1 Pre-travel 1 Antirelapse therapy for P. ovale *Off-label: Presumptive antirelapse therapy (when suppressive chemoprophylaxis used)

Future Investigations � Adverse events Thank you! � Postmarketing surveillance studies (required by FDA) � MedWatch – FDA’s adverse event reporting system � Long-term safety study � Use in children � Efficacy for antirelapse therapy with artemisinin combination drug 1600 Clifton Road NE, Atlanta, GA 30333 Telephone, 1-800-CDC-INFO (232-4636)/TTY: 1-888-232-6348 Web: www.cdc.gov The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention. Center for Global Health Division of Parasitic Diseases and Malaria