Tafenoquine for Malaria Disclosure: Prophylaxis and Antirelapse - - PDF document

Tafenoquine for Malaria Prophylaxis and Antirelapse Therapy

Kathrine R. Tan MD, MPH

CISTM June 6, 2019

Disclosure: Co-investigator on postmarketing surveillance for adverse events of tafenoquine (Krintafel) labeled for antirelapse therapy in the U.S. No financial disclosures

Plasmodium Life Cycle (Abridged)

>1 month later (P. vivax, P. ovale) <1 month later

• P. vivax — Widest Geographic Distribution of the Human Malarias

• P. vivax can cause severe disease and death

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)

Most Antimalarials Don’t Kill Hypnozoites

Atovaquone-proguanil Artemisinins Chloroquine Doxycycline Mefloquine Quinine Primaquine

• P. vivax
• P. ovale

Weeks after departure 1 4

• P. falciparum

Hypnozoites and Malaria Prophylaxis

Chloroquine Doxycycline Mefloquine Atovaquone-proguanil

• P. vivax
• P. ovale

Weeks after departure 1 4

• P. falciparum

Hypnozoites and Malaria Prophylaxis

(AP) Chloroquine Doxycycline Mefloquine Atovaquone-proguanil

• P. vivax
• P. ovale

Weeks after departure 1 4

• P. falciparum

Hypnozoites and Malaria Prophylaxis

(AP) Primaquine (off label)

Hypnozoites and Treatment of P. vivax and P. ovale

Schizontozide Hypnozoitocide (until recently, only option primaquine x 14 days)

Chloroquine Doxycycline Mefloquine Atovaquone-proguanil Weeks after departure 1 4

Lengthy Regimen May Challenge Adherence

Prophylaxis Treatment (P. vivax, P. ovale) Day of treatment 1 2 3 15 Chloroquine Primaquine

8-aminoquinolines Development to Approval

Primaquine developed and approved 1950 Korean War 1960 Vietnam War 1990 2010 2020 1980 Tafenoquine developed and approved 1970 2000 In the U.S.: Arakoda — Prophylaxis Krintafel — Antirelapse therapy 1940 World War II

8-aminoquinolines Half-lives

Primaquine Half-life: 15 days Tafenoquine Half-life: 6 hours

Prophylaxis: What Dose? (Semi-immune Adults)

Regimen (n) Protective efficacy (95% CI) Placebo (59) Ref. TQ 400 mg x 3 days, then placebo weekly (54) 68% (53–79%) TQ 200 mg x 3 days, then 200 mg weekly (53) 86% (73–93%) TQ 400 mg x 3 days, then 400 mg weekly (57) 89% (77–95%)

Prophylaxis: Minimum Maintenance Dose (Semi-immune Adults)

Regimen (n) Protective efficacy (95% CI) Placebo (94) Ref. MQ 250 mg weekly (46) 86% (72-93%) 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%) 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%)

Prophylaxis: Efficacy Tafenoquine vs Mefloquine (Non-immune Adults)

TQ (N=492) MQ (N=162) Success 468 (95.1%) 156 (96.3%) Failure (P. vivax) 4 (0.8%) 1 (0.6%) Missing 20 (4.1%) 5 (3.1%) Difference in success proportion (TQ-MQ) [95%CI]: -1.2% [-4.7%, 2.3%] Prophylactic outcome during the study (50 weeks)

Prophylaxis: Activity Against P. falciparum Schizonts

1 Day 32 10 2 3 13 T T T T P P P P

Antirelapse Therapy: What Dose? DETECTIVE Part 1

Placebo 38% (23–– 52) PQ 15mgx14d 77% (63–– 87) TQ 300 mg 89% (77–95) TQ 600 mg 92% (80––97)

Relapse free at 6 months

Antirelapse Therapy: Efficacy of Tafenoquine vs Placebo DETECTIVE Part 2

Antirelapse Therapy: Efficacy of Tafenoquine vs Primaquine GATHER Meta-Analysis

Relapse free at 6 months Primaquine 73% (66–79) Tafenoquine 67% (61–72)

Hemolytic Anemia and Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency

G6PD Activity Normal Deficient Intermediate

X Y

• O

X Y + O X X + + X X

• -

X X + -

Hemolytic Anemia and Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency

G6PD Activity Normal Deficient Intermediate

X Y

• O

X Y + O X X + + X X

• -

X X + -

Missed by qualitative tests

Adverse Events at Prophylactic Doses* N=825

*U.S. Food and Drug Administration (FDA) safety review and report

Adverse events in >2%

GI: Diarrhea, nausea, vomiting Neuro: Headache, dizziness Psychiatric adverse events Not of clinical significance: Methemoglobinemia, vortex keratopathy

Adverse events in <2% but of interest

Hypersensitivity reactions

Psychiatric Adverse Events* (Prophylactic Doses)

*FDA safety review and report

Observed in 4% Most common: Insomnia (1.2%), weird dreams (0.6%), anxiety (0.2%) Other adverse events (all with prior history):

Depression/depressed mood (3 cases) Attempted suicide (1 case)

Adverse Events at Antirelapse Therapy Dose (N=483)

Adverse events >2%

GI: Diarrhea, nausea vomiting Neuro: Headache, dizziness Psychiatric adverse events Not of clinical significance: Methemoglobinemia

Psychiatric adverse events 3%

Insomnia Anxiety <1% No severe events

*FDA safety review and report

Adverse Reactions on Labels

Delayed presentation possible — long half-life GI: Diarrhea, nausea, vomiting, increased liver enzymes Neuro: Headache, dizziness Heme: Decreased hemoglobin Musculoskeletal: Back pain Psych: Insomnia, abnormal dreams, anxiety, depression

Contraindications and Warnings

G6PD deficiency

Pregnant women (unknown status fetus) Breastfeeding women (if infant status unknown, or deficient)

History of psychiatric illness Known hypersensitivity

Tafenoquine in Practice

Consider criteria:

Adult (≥ 16 years old for antirelapse therapy) Not pregnant Not breastfeeding (or if breastfeeding infant with normal G6PD) No history of psychiatric illness No known hypersensitivity to 8-aminoquinolines

Do quantitative G6PD testing If normal quantitative G6PD test – OK to give

= 100 mg

Short-Term (<6 months) Prophylaxis All Species of Malaria in Adults (Arakoda in U.S.)

Pre-travel

• 1

Week Travel 3 Post-travel 1 2 Travel

Antirelapse Therapy for P. vivax Malaria* in ≥ 16 year olds (Krintafel in U.S.)

= 150 mg

Day of treatment 1 2 3 Chloroquine Tafenoquine *Off-label: Antirelapse therapy for P. ovale Presumptive antirelapse therapy (when suppressive chemoprophylaxis used)

Future Investigations

Adverse events

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

Thank you!