Primaquine 2.5mg/5ml oral suspension

BackgroundAdding a single dose of primaquine to artemisinin-based combination therapy (ACT) for the treatment of falciparum malaria can reduce the transmission of Plasmodium falciparum and could limit the spread of artemisinin partial resistance, including in Africa, where the disease burden is greatest. We aimed to compare the safety and efficacy of single-dose primaquine plus ACT between young children (aged MethodsFor this systematic review and individual patient data meta-analysis, we searched PubMed, Embase, Web of Science, Cochrane Central Register of Controlled Trials, WHO Global Index Medicus, OpenGrey.eu, ClinicalTrials.gov, and the WHO International Clinical Trials Registry Platform, from database inception to April 3, 2024, with no language restrictions. We included prospective studies on efficacy against falciparum malaria that enrolled at least one child younger than 15 years and involved a study group given a single dose of primaquine (≤0·75 mg/kg) plus ACT. Studies involving mass drug administration, healthy volunteers, or patients with severe malaria or mixed (with non-falciparum) infections were excluded. For inclusion in the efficacy analysis, data on transmission potential (as determined by gametocytaemia, infectivity, or both) at enrolment and follow-up (day 3, day 7, or day 14) were required; the safety analysis required data on haemoglobin concentrations or haematocrit values at enrolment and at one or more follow-up visits by day 7, any data on adverse events, or both. After independent screening of the search results by two reviewers, the investigators of eligible studies were invited to contribute individual patient data. We quantified day 7 gametocyte carriage, probability of infecting a mosquito, decreases (>25%) in haemoglobin concentration associated with anaemia, and adverse events until day 28 using regression analyses, with random study-site intercepts to account for clustered data. These analyses were registered with PROSPERO, CRD42021279363 (safety) and CRD42021279369 (efficacy).FindingsOf 5697 records identified by the search, 30 studies were eligible for analysis. Of these, individual patient data were shared for 23 studies, including 6056 patients from 16 countries: 1171 (19·3%) young children (aged 25%) at a primaquine dose of 0·25 mg/kg, regardless of age group, transmission setting, and glucose-6-phosphate dehydrogenase status. The risks of adverse events of grade 2 or higher and of serious adverse events were similar between primaquine and no-primaquine groups, including in young children.InterpretationRegardless of malaria transmission intensity and age group, a single dose of 0·25 mg/kg primaquine is safe and efficacious for reducing P falciparum transmission. These findings underscore the need for primaquine formulations suitable for young children, and also provide supportive evidence to expand the use of single low-dose primaquine in regions with a moderate-to-high transmission rate that are threatened by artemisinin partial resistance.FundingThe EU and the Bill & Melinda Gates Foundation.

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BackgroundThe 8-aminoquinoline antimalarials are used to prevent P. vivax relapses. Recent evidence suggests high total dose primaquine (7 mg/kg) provides optimal efficacy, however, many countries, including Ethiopia, use low total dose primaquine (3.5 mg/kg). To understand the risks and benefits of different primaquine dosing regimens for P. vivax malaria in Ethiopia, we undertook a systematic review and individual patient data meta-analysis.MethodsWe searched for antimalarial efficacy studies in patients with uncomplicated P. vivax mono-infections conducted in Ethiopia, published between January 1, 2000, and March 8, 2024. Studies were included if they had at least 28 days of follow-up and included a treatment arm with daily primaquine, commenced within seven days of starting antimalarial treatment. Study investigators were approached to share individual patient data, which were standardised and pooled. We performed a one-stage meta-analysis to estimate the cumulative incidence of P. vivax recurrence by day 180 with different primaquine total dose regimens. The number and proportion of gastrointestinal symptoms on days 5-7 and clinically significant haemolysis within 14 days were described and stratified by daily primaquine dose. PROSPERO CRD42023491851.ResultsOf 297 identified studies, 5 were eligible for inclusion. Data from 1,378 patients from all 5 studies were obtained. The cumulative incidence of P. vivax recurrence by day 180 was 61.0% (95%CI: 55.3-66.8) in patients who were not treated with primaquine, 16.6% (12.0-22.7) following low total dose and 8.9% (6.4-12.4) following high total dose primaquine. High total dose primaquine (7 mg/kg) was associated with a reduced rate of recurrence compared with low total dose (3.5 mg/kg) (Adjusted Hazard Ratio 0.40; 95% CI 0.24-0.68, p = 0.001). Gastrointestinal disturbance on days 5-7 was recorded in 20/104 (19.1%) patients without primaquine, 36/225 (16.0%) patients treated with 0.5 mg/kg primaquine daily and 54/224 (24.1%) patients treated with 1 mg/kg primaquine daily. In patients with normal G6PD activity (≥ 30%), one patient had a ≥ 25% fall in haemoglobin to  5 g/dL fall, one following 0.5 mg/kg daily and one following 1 mg/kg daily.ConclusionsLow and high total dose primaquine reduced the risk of recurrence of P. vivax malaria substantially in Ethiopia compared with no primaquine, with high total dose regimens conferring greater protection. All doses demonstrated acceptable tolerability and clinically significant haemolytic events were uncommon in patients with ≥ 30% G6PD activity.

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Summary Background Plasmodium vivax malaria has diverse transmission and relapse patterns in Indonesia. The optimal dose of primaquine to prevent relapses across the country is unknown. We evaluated the anti-relapse efficacy, gastrointestinal tolerability, and haematological safety of different primaquine regimens in varied endemic settings in Indonesia. Methods We systematically searched for studies published between 1 January 2000 and 23 July 2024 prospectively enrolling patients with acute uncomplicated P. vivax malaria where some patients were treated with primaquine. Individual patient data (IPD) from eligible studies were pooled and harmonised. We fitted one-stage IPD multivariable regression models to estimate the relationship between the weight-adjusted primaquine dose with three separate primary outcomes: (i) the time to first P. vivax recurrence (days 7–180), (ii) any gastrointestinal discomfort (days 5–7), and (iii) ≥25% reduction relative to baseline haemoglobin and a reduction to Findings Of ten eligible studies, seven were available for inclusion. Compared with a total dose of 3·5 mg/kg primaquine, patients treated with a total dose of 7 mg/kg had a lower rate of recurrence over 6 months (adjusted hazard ratio 0·53; 95% confidence interval [CI] 0·45 to 0·63; n = 1797); the relative efficacy was consistent across regions, but the absolute benefit varied. Gastrointestinal discomfort was more frequent with higher doses (adjusted risk ratio 1·32 per 0·25 mg/kg daily dose; 95% CI 1·15 to 1·51; n = 952). For haematological safety (n = 822; 788/822 [96%] patients had G6PD activity ≥70%), only one patient developed clinically relevant haemolysis. Interpretation Across all transmission settings in Indonesia, a total dose of 7 mg/kg halved the rate of recurrent P. vivax malaria over a 6-month period compared with the low dose of 3·5 mg/kg. However, increased daily doses slightly increased risks of gastrointestinal discomfort and haemolysis. Funding NDM Tropical Network Fund, Bill and Melinda Gates Foundation Research in context Evidence before this study Indonesia is a geographically vast country with heterogeneous patterns of periodicity and varying magnitudes of risk for Plasmodium vivax relapse. However, the optimal regimen for the radical cure of P. vivax is unknown. The national antimalarial guidelines continue to recommend a low-dose regimen of 3·5 mg/kg without routine glucose-6-phosphate dehydrogenase (G6PD) testing. We systematically searched for trials conducted in Indonesia that randomly assigned patients with P. vivax malaria to primaquine dosing regimens. Articles published in any language between 1 January 2000 and 23 July 2024, using the terms “vivax” and “primaquine” in MEDLINE, Embase, Web of Science, Scopus, and the Cochrane Library were identified. No published randomised controlled trial directly comparing high-dose (≥5 mg/kg total) versus low-dose (2 to Added value of this study This country-specific systematic review and individual patient data meta-analysis included 1797 patients from seven studies evaluating anti-relapse efficacy, gastrointestinal tolerability, and haematological safety. The analysis represents the most comprehensive analysis to date of different primaquine dosing regimens for P. vivax malaria in Indonesia. The results suggest that doubling the total dose from 3·5 mg/kg to 7 mg/kg would halve the rate of P. vivax recurrence within 180 days, however, the absolute benefit of this reduction depends on the underlying risk of recurrence in different regions of Indonesia. An increase in the daily dose of primaquine resulted in a moderate increase in gastrointestinal discomfort; and only a rare occurrence of clinically relevant haemolysis, given that G6PD activity among patients was mostly ≥70%. Implication of all the available evidence For Indonesian patients with P. vivax malaria, a high total primaquine dose of 7 mg/kg is more efficacious than the currently implemented 3·5 mg/kg regimen. Higher daily doses of primaquine are associated with increased gastrointestinal discomfort, however, these may be mitigated by co-administration with food. Clinically relevant haemolysis is rare in patients with G6PD activity >30%.

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BackgroundThe antirelapse efficacy of primaquine is related to the total dose administered, whereas the risks of haemolysis and gastrointestinal intolerance are associated with the daily dose administered. National Malaria Control Programmes require local information on efficacy, tolerability and safety to optimize antimalarial treatment policies for Plasmodium vivax malaria control and elimination efforts.MethodsA living systematic review identified efficacy studies of uncomplicated P. vivax malaria including patients treated with daily primaquine regimens, published since January 1, 2000. Available data were pooled and an R Shiny app was developed to integrate statistical analyses performed using R and Stata that assessed the impact of primaquine mg/kg dose on efficacy, hematological safety and gastrointestinal tolerability.ResultsAs of January 16, 2025, a total of 9,270 individual patient data records from 41 studies have been collated into the standardized repository. Open-access automated reports were generated for user-selected countries or regions to investigate location specific effects of primaquine dose on efficacy, safety and tolerability. The reports include visual and tabular displays of the outcomes.ConclusionsThese automated reports leverage a large database to provide accessible data for national and regional policy makers and researchers to assess the clinical consequences of different primaquine regimens in different endemic settings. The reports will inform local and regional policy decisions and research priorities in vivax-endemic areas.

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