8 Aminoquinoline Antimalarials

The 8-aminoquinolines (primaquine and tafenoquine) are the only antimalarials that kill the dormant liver stages (hypnozoites) of Plasmodium vivax and ovale, and they also kill mature gametocytes of falciparum malaria. They are activated by CYP2D6, and they cause haemolysis in G6PD deficiency, which limits their use.

Pharmacokinetics. Primaquine is absorbed orally with a half-life of about 6 hours. Tafenoquine has a half-life of about 15 days, which allows a single dose.

• Primaquine: radical cure of vivax and ovale, 15 mg (0.25 mg/kg) daily for 14 days, or 0.5 mg/kg daily for 7 days in regions with short-latency strains. Take with food.
• Primaquine for falciparum transmission blocking: single dose 0.25 mg/kg (about 15 mg for an adult) with the combination.
• Tafenoquine: single 300 mg dose for radical cure of vivax in patients 16 years and over, given with chloroquine or a combination; needs quantitative G6PD of at least 70% of normal.
• Tafenoquine prophylaxis: 200 mg daily for 3 days, then weekly; avoided in many travellers because of G6PD and neuropsychiatric limits.

G6PD testing. Test before radical cure where possible. The African variant (A minus) causes mild to moderate haemolysis, and primaquine 0.75 mg/kg once weekly for 8 weeks is an option under specialist direction. The single low dose for falciparum is safe in this variant.

Selection.

• Vivax and ovale: chloroquine or a combination, plus primaquine 14 days.
• Relapse after treatment: repeat with a higher or longer primaquine course.
• Severe G6PD deficiency (Mediterranean variant): avoid primaquine and tafenoquine.

CYP2D6. Poor metabolisers have reduced efficacy. Avoid CYP2D6 inhibitors (fluoxetine, paroxetine, terbinafine) where possible.

Children. Primaquine 0.25 mg/kg daily for 14 days from 6 months of age; tafenoquine in children under 16 is limited to weight-based licensed products.

Region. In East Africa, vivax is mainly in the Horn of Africa. G6PD deficiency is common in many African populations, usually the mild A minus form.

Contraindications. Pregnancy; breastfeeding unless the infant is G6PD normal; infants under 6 months; severe G6PD deficiency; tafenoquine with psychotic illness.

Serious adverse effects. Dose-related haemolysis (dark urine, pallor, jaundice) usually in the first 2 to 8 days; methaemoglobinaemia (with NADH methaemoglobin reductase deficiency); nausea and abdominal pain; QT prolongation (primaquine); neuropsychiatric effects with tafenoquine.

Monitoring. Haemoglobin and urine colour at day 3 and day 7; stop for a fall in haemoglobin of more than 3 g/dL, a level under 7 g/dL, or dark urine.

Interactions. CYP2D6 inhibitors; drugs that cause haemolysis or methaemoglobinaemia (dapsone, sulphonamides, nitrofurantoin).

Special groups.

• Pregnancy: delay radical cure until after delivery; use weekly chloroquine suppression for vivax in the meantime.
• Breastfeeding: delay until infant G6PD status is known.
• Kidney and liver impairment: use with caution.

Referral and escalation. Refer haemolysis, repeated relapse, or uncertain G6PD status in pregnancy or infancy.