Single Low-Dose Primaquine for Plasmodium falciparum Malaria Treated with ACT
Yes, a single low-dose primaquine (0.25 mg/kg, approximately 45 mg for adults) should be added to artemisinin-based combination therapy for uncomplicated P. falciparum malaria to block transmission, particularly in areas threatened by artemisinin resistance or low transmission settings where symptomatic infections contribute substantially to ongoing transmission. 1, 2
Rationale for Adding Primaquine to ACT
The World Health Organization recommends adding a single gametocytocidal dose of primaquine (0.25 mg/kg) to ACT regimens for uncomplicated P. falciparum malaria in areas of low transmission or artemisinin resistance. This recommendation aims to reduce the infectious reservoir and counter the spread of resistant parasites. 3, 4
Single low-dose primaquine (0.25 mg/kg) achieves near-complete prevention of transmission to mosquitoes when combined with ACT. An individual patient meta-analysis of 2,574 participants from 14 studies demonstrated that primaquine reduced PCR-determined gametocyte carriage on days 7 and 14, with the strongest effect in patients presenting with baseline gametocytemia (OR 0.22 on day 7; OR 0.12 on day 14). 5
Primaquine provides unique gametocytocidal activity by rapidly sterilizing mature transmissible stages of P. falciparum. While ACTs reduce gametocyte carriage, artemisinin resistance lessens overall gametocytocidal activity, creating selective pressure for resistant parasite spread. Adding primaquine counters this effect. 4
Dosing and Administration
The recommended dose is 0.25 mg/kg (approximately 45 mg for a 60 kg adult) given as a single dose concomitantly with the first dose of ACT. 3, 6, 7
Primaquine should be administered with the first ACT dose to maximize transmission-blocking efficacy. In one Cambodian trial, a single 45 mg dose given after the third dose of dihydroartemisinin-piperaquine showed a two-fold reduction in oocyst density in infected mosquitoes within 24 hours. 6
The transmission-blocking effect is rapid and substantial. A Myanmar trial demonstrated that adding 0.75 mg/kg primaquine reduced P. falciparum gametocyte carriage with a rate ratio of 11.9 (95% CI 7.4–20.5). 3
Safety Profile and G6PD Considerations
Single low-dose primaquine (0.25 mg/kg) is safe for treatment of uncomplicated P. falciparum malaria regardless of G6PD status, according to WHO recommendations and supporting trial data from Tanzania. 7
In a randomized trial of 220 Tanzanian patients (15.2% phenotypically G6PD deficient), the mean relative hemoglobin reduction on day 7 was not statistically significant in G6PD-deficient patients receiving primaquine plus artemether-lumefantrine compared to artemether-lumefantrine alone. None of the patients met the pre-defined hemolytic threshold of ≥25% hemoglobin reduction. 7
Six episodes (4.4%) of acute hemolytic anemia occurred between days 0 and 7 (three per treatment arm), with three in phenotypically G6PD-deficient patients but none in genotypically hemizygous/homozygous patients. All recovered without medical intervention. 7
G6PD testing is NOT required before administering single low-dose (0.25 mg/kg) primaquine for P. falciparum malaria. This contrasts sharply with the 14-day primaquine regimen for P. vivax radical cure, where G6PD testing is mandatory. 7
Contraindications for Single Low-Dose Primaquine
Absolute contraindications include pregnancy, breastfeeding women with infants under 6 months, and infants under 6 months of age. 8
Severe G6PD deficiency is NOT an absolute contraindication for the single low-dose (0.25 mg/kg) regimen used for P. falciparum transmission blocking, based on WHO guidance and safety data. However, clinical judgment should be exercised in patients with known severe deficiency variants. 7
ACT-Specific Considerations
Gametocyte persistence and infectivity are lower when primaquine is combined with artemether-lumefantrine compared to dihydroartemisinin-piperaquine. The rate of decline in gametocyte carriage was faster with artemether-lumefantrine plus primaquine (p=0.010 for day 7). 5
In settings of established ACT resistance, primaquine becomes even more critical. A Cambodian trial in an area of dihydroartemisinin-piperaquine resistance showed that primaquine rapidly reduced gametocytemia, while dihydroartemisinin-piperaquine alone failed to reduce gametocytemia and prevent transmission to mosquitoes through day 14. 6
Common Pitfalls to Avoid
Do not confuse the single low-dose (0.25 mg/kg) primaquine regimen for P. falciparum transmission blocking with the 14-day (0.5 mg/kg/day) regimen for P. vivax radical cure. The former does NOT require G6PD testing; the latter absolutely does. 8, 7
Do not withhold single low-dose primaquine due to unavailability of G6PD testing in P. falciparum malaria. The WHO recommendation explicitly allows administration regardless of G6PD status for this indication. 7
Do not overlook pregnancy screening before primaquine administration. Primaquine is absolutely contraindicated in pregnancy for any indication. 8
Recognize that microscopic gametocytemia is an excellent predictor of infectiousness post-treatment. In the Cambodian trial, none of 474 mosquitoes infected post-treatment arose from submicroscopic gametocytes, making microscopy a practical tool for assessing transmission risk. 6
Be aware that mixed P. falciparum/P. vivax infections are common in some endemic areas. In the Myanmar trial, 16% had mixed infection at presentation and 41% developed P. vivax during 63-day follow-up, highlighting that single low-dose primaquine does NOT provide radical cure for P. vivax hypnozoites. 3