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Primaquine: the risks and the benefits.

Ashley EA, Recht J, White NJ - Malar. J. (2014)

Bottom Line: In six decades of primaquine use in approximately 200 million people, 14 deaths have been reported.Confining the estimate to reports with known denominators gives an estimated mortality of one in 621,428 (upper 95% CI: one in 407,807).All but one death followed multiple dosing to prevent vivax malaria relapse.

View Article: PubMed Central - PubMed

Affiliation: Mahidol-Oxford Tropical Medicine Research Unit (MORU), Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand. nickw@tropmedres.ac.

ABSTRACT
Primaquine is the only generally available anti-malarial that prevents relapse in vivax and ovale malaria, and the only potent gametocytocide in falciparum malaria. Primaquine becomes increasingly important as malaria-endemic countries move towards elimination, and although it is widely recommended, it is commonly not given to malaria patients because of haemolytic toxicity in subjects who are glucose-6-phosphate dehydrogenase (G6PD) deficient (gene frequency typically 3-30% in malaria endemic areas; >180 different genetic variants). In six decades of primaquine use in approximately 200 million people, 14 deaths have been reported. Confining the estimate to reports with known denominators gives an estimated mortality of one in 621,428 (upper 95% CI: one in 407,807). All but one death followed multiple dosing to prevent vivax malaria relapse. Review of dose-response relationships and clinical trials of primaquine in G6PD deficiency suggests that the currently recommended WHO single low dose (0.25 mg base/kg) to block falciparum malaria transmission confers a very low risk of haemolytic toxicity.

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Related in: MedlinePlus

Primaquine-induced haemolysis in adults with different G6PD variants during daily dosing. Primaquine was given daily for 14 days at a dose of 30 mg/day in individuals with Mediterranean and African A-variants [18, 21] and 15 mg/day for Mahidol or Viangchan variants [22, 23]. The effects of a 45-mg single primaquine dose in individuals with either Mahidol or Viangchan variants are shown for comparison [24]. This figure uses data derived from different studies as referenced.
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Fig1: Primaquine-induced haemolysis in adults with different G6PD variants during daily dosing. Primaquine was given daily for 14 days at a dose of 30 mg/day in individuals with Mediterranean and African A-variants [18, 21] and 15 mg/day for Mahidol or Viangchan variants [22, 23]. The effects of a 45-mg single primaquine dose in individuals with either Mahidol or Viangchan variants are shown for comparison [24]. This figure uses data derived from different studies as referenced.

Mentions: Dosing of primaquine is limited by abdominal discomfort at doses over 1 mg/kg. In general, primaquine is well tolerated at individual doses ≤0.5 mg base/kg if given together with food. Some methaemoglobinaemia is common, but very seldom is dangerous. The main adverse effect of primaquine is oxidant haemolysis. Although some red cell loss may occur in normal subjects, patients who are G6PD deficient are particularly vulnerable. It is the potential for toxicity in G6PD deficiency that has limited the use of primaquine. There are over 180 different genetic G6PD variants, nearly all conferring an unstable enzyme, which degrades more rapidly than the normal variant thereby rendering older red cells vulnerable to oxidant damage [12, 13]. The extent of haemolysis depends on the degree of G6PD deficiency and the dose and duration of exposure to primaquine. Two of the most prevalent G6PD variants represent ends of the severity spectrum with the Mediterranean variant (the main variant found in Europe, west and central Asia, and northern India) being amongst the most profound deficiencies, and the African A- variant (found in sub-Saharan Africa and in African-Americans) being amongst the mildest. Severe haemolytic reactions can still occur in G6PDA-, but they are much less frequent. Haemolytic risks vary widely as there is also substantial variability in G6PD activity between individuals with the same genotype, and even within the same individual over time. In less severe G6PD variants, primaquine-induced haemolysis typically becomes evident after one or two days’ exposure, when all the older erythrocytes’ oxidant defences (mainly reduced glutathione) have been depleted [14]. If primaquine is continued in subjects with the African A- variant then haemolysis lessens, and the haemoglobin starts to rise again despite further drug administration, as reticulocytes enter the circulation to replace the haemolysed cells (Figure 1) [15]. These young red cells contain five times more G6PD than the oldest red cells and so are relatively resistant to the haemolytic effect. However, further haemolysis does occur if higher doses of primaquine are given [16]. In contrast, in the severe Mediterranean variant, haemolysis continues if primaquine is not stopped and life-threatening anaemia may result (Figure 1) [17, 18]. Although the pathophysiology of primaquine haemolysis was dissected in detail in classic studies conducted in the 1950s and 1960s [14–20], several outstanding questions remain. Are patients with malaria at greater or lesser risk of haemolysis than healthy subjects? Does pre-existing hookworm or malaria-related anaemia reduce haemolysis? What exactly are the risks associated with the different therapeutic regimens? What reductions in haemoglobin are life threatening? There are also uncertainties over P. vivax relapse rates and latency intervals across much of the tropics which complicate therapeutic assessments, the methods for assessing gametocytocidal effects and their interpretation in clinical evaluations are disputed, and the community benefits from deployment of primaquine as a single dose gametocytocide have not been well characterized.Figure 1


Primaquine: the risks and the benefits.

Ashley EA, Recht J, White NJ - Malar. J. (2014)

Primaquine-induced haemolysis in adults with different G6PD variants during daily dosing. Primaquine was given daily for 14 days at a dose of 30 mg/day in individuals with Mediterranean and African A-variants [18, 21] and 15 mg/day for Mahidol or Viangchan variants [22, 23]. The effects of a 45-mg single primaquine dose in individuals with either Mahidol or Viangchan variants are shown for comparison [24]. This figure uses data derived from different studies as referenced.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4230503&req=5

Fig1: Primaquine-induced haemolysis in adults with different G6PD variants during daily dosing. Primaquine was given daily for 14 days at a dose of 30 mg/day in individuals with Mediterranean and African A-variants [18, 21] and 15 mg/day for Mahidol or Viangchan variants [22, 23]. The effects of a 45-mg single primaquine dose in individuals with either Mahidol or Viangchan variants are shown for comparison [24]. This figure uses data derived from different studies as referenced.
Mentions: Dosing of primaquine is limited by abdominal discomfort at doses over 1 mg/kg. In general, primaquine is well tolerated at individual doses ≤0.5 mg base/kg if given together with food. Some methaemoglobinaemia is common, but very seldom is dangerous. The main adverse effect of primaquine is oxidant haemolysis. Although some red cell loss may occur in normal subjects, patients who are G6PD deficient are particularly vulnerable. It is the potential for toxicity in G6PD deficiency that has limited the use of primaquine. There are over 180 different genetic G6PD variants, nearly all conferring an unstable enzyme, which degrades more rapidly than the normal variant thereby rendering older red cells vulnerable to oxidant damage [12, 13]. The extent of haemolysis depends on the degree of G6PD deficiency and the dose and duration of exposure to primaquine. Two of the most prevalent G6PD variants represent ends of the severity spectrum with the Mediterranean variant (the main variant found in Europe, west and central Asia, and northern India) being amongst the most profound deficiencies, and the African A- variant (found in sub-Saharan Africa and in African-Americans) being amongst the mildest. Severe haemolytic reactions can still occur in G6PDA-, but they are much less frequent. Haemolytic risks vary widely as there is also substantial variability in G6PD activity between individuals with the same genotype, and even within the same individual over time. In less severe G6PD variants, primaquine-induced haemolysis typically becomes evident after one or two days’ exposure, when all the older erythrocytes’ oxidant defences (mainly reduced glutathione) have been depleted [14]. If primaquine is continued in subjects with the African A- variant then haemolysis lessens, and the haemoglobin starts to rise again despite further drug administration, as reticulocytes enter the circulation to replace the haemolysed cells (Figure 1) [15]. These young red cells contain five times more G6PD than the oldest red cells and so are relatively resistant to the haemolytic effect. However, further haemolysis does occur if higher doses of primaquine are given [16]. In contrast, in the severe Mediterranean variant, haemolysis continues if primaquine is not stopped and life-threatening anaemia may result (Figure 1) [17, 18]. Although the pathophysiology of primaquine haemolysis was dissected in detail in classic studies conducted in the 1950s and 1960s [14–20], several outstanding questions remain. Are patients with malaria at greater or lesser risk of haemolysis than healthy subjects? Does pre-existing hookworm or malaria-related anaemia reduce haemolysis? What exactly are the risks associated with the different therapeutic regimens? What reductions in haemoglobin are life threatening? There are also uncertainties over P. vivax relapse rates and latency intervals across much of the tropics which complicate therapeutic assessments, the methods for assessing gametocytocidal effects and their interpretation in clinical evaluations are disputed, and the community benefits from deployment of primaquine as a single dose gametocytocide have not been well characterized.Figure 1

Bottom Line: In six decades of primaquine use in approximately 200 million people, 14 deaths have been reported.Confining the estimate to reports with known denominators gives an estimated mortality of one in 621,428 (upper 95% CI: one in 407,807).All but one death followed multiple dosing to prevent vivax malaria relapse.

View Article: PubMed Central - PubMed

Affiliation: Mahidol-Oxford Tropical Medicine Research Unit (MORU), Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand. nickw@tropmedres.ac.

ABSTRACT
Primaquine is the only generally available anti-malarial that prevents relapse in vivax and ovale malaria, and the only potent gametocytocide in falciparum malaria. Primaquine becomes increasingly important as malaria-endemic countries move towards elimination, and although it is widely recommended, it is commonly not given to malaria patients because of haemolytic toxicity in subjects who are glucose-6-phosphate dehydrogenase (G6PD) deficient (gene frequency typically 3-30% in malaria endemic areas; >180 different genetic variants). In six decades of primaquine use in approximately 200 million people, 14 deaths have been reported. Confining the estimate to reports with known denominators gives an estimated mortality of one in 621,428 (upper 95% CI: one in 407,807). All but one death followed multiple dosing to prevent vivax malaria relapse. Review of dose-response relationships and clinical trials of primaquine in G6PD deficiency suggests that the currently recommended WHO single low dose (0.25 mg base/kg) to block falciparum malaria transmission confers a very low risk of haemolytic toxicity.

Show MeSH
Related in: MedlinePlus