What is the recommended dose of primaquine for the treatment of Plasmodium vivax malaria?

Primaquine Dosing for Plasmodium vivax Malaria

For radical cure of P. vivax malaria in G6PD-normal adults, administer primaquine 30 mg base daily (0.5 mg/kg/day) for 14 days concurrently with chloroquine or an artemisinin-based combination therapy. 1, 2

Standard Dosing Regimens

Adults (G6PD-Normal)

• High-standard dose (preferred): 30 mg base daily (0.5 mg/kg/day) for 14 days 1, 2
• Alternative standard dose: 15 mg base daily (0.25 mg/kg/day) for 14 days 3, 2
  • This lower dose may be insufficient for Southeast Asian P. vivax strains, where recurrence rates can reach 24% compared to only 5% with the high-standard dose 4

Children (G6PD-Normal)

• Recommended dose: 0.3 mg/kg/day for 14 days 3
• Alternative high-standard dose: 0.5 mg/kg/day for 14 days 3, 1

Critical Pre-Treatment Requirements

G6PD Testing is Mandatory

• G6PD testing must be performed before primaquine administration to prevent life-threatening hemolysis 3, 1
• Primaquine causes severe hemolytic anemia in patients with G6PD deficiency, which can be fatal 3
• In Asian populations where severe G6PD deficiency is common, primaquine should not be given for more than 5 days without G6PD testing 3

Absolute Contraindications

• Pregnancy 1
• Breastfeeding women 1
• Infants less than 6 months old 1
• Severe G6PD deficiency (without dose modification) 1

Modified Dosing for G6PD Deficiency

For Mild to Moderate G6PD Deficiency (30-70% activity)

• Weekly regimen: 45 mg base (0.75 mg/kg) once weekly for 8 weeks 3, 1
• This reduces hemolysis risk while maintaining anti-hypnozoite efficacy 1

Alternative Shortened Regimens (G6PD-Normal Only)

Seven-Day High-Dose Regimen

• Dose: 0.5 mg/kg/day (total 210 mg adult dose) for 7 days 5, 6, 7
• Recurrence rates are similar to the standard 14-day regimen at 0.25 mg/kg/day (RR 0.96,95% CI 0.66-1.39) 5, 6
• This regimen may improve adherence in patients who struggle with 14-day courses 5, 6
• No serious adverse events reported in G6PD-normal patients 5, 6

Seven-Day Ultra-High-Dose Regimen

• Dose: 1.0 mg/kg/day for 7 days 6, 7
• Probably similar efficacy to high-standard 0.5 mg/kg/day for 14 days (RR 1.03,95% CI 0.82-1.30) 6
• May cause more serious adverse events (RR 12.03,95% CI 1.57-92.30) compared to the 14-day high-standard regimen 6
• Should be used with caution 6, 7

Clinical Implementation

Timing and Co-Administration

• Start primaquine concurrently with blood schizontocidal treatment (chloroquine or ACT) 1, 2
• Co-administration with chloroquine boosts primaquine blood levels, enhancing efficacy 1
• Primaquine is administered after or during chloroquine blood-phase therapy 3

Monitoring Requirements

• Monitor for hemolysis signs: dark urine, jaundice, fatigue, particularly in the first week 1
• Clinical improvement should occur within 48 hours of starting treatment 1
• Perform follow-up blood smears to confirm parasite clearance 1
• Check hematocrit, especially in G6PD heterozygous females who may require blood transfusion if hematocrit drops below 23% 7

Regional Considerations

Southeast Asian and Oceanic Strains

• Use the high-standard dose (0.5 mg/kg/day for 14 days) in these regions 1, 4
• The lower 0.25 mg/kg/day dose results in 24% recurrence rates versus only 5% with the higher dose in Cambodia 4
• The hazard ratio for recurrence with high-dose versus low-dose primaquine is 0.17 (95% CI 0.04-0.79) 4

Areas with Low Reinfection Risk

• Primaquine supplementation should be considered for all P. vivax cases 3
• Without primaquine, recurrence rates can reach 81% within 90 days 4

Safety Profile

In G6PD-Normal Individuals

• Both standard (0.25 mg/kg/day) and high-standard (0.5 mg/kg/day) 14-day regimens are well-tolerated with comparable safety profiles 1, 4
• Adverse events are typically mild and transient 8
• Treatment-limiting adverse events are rare 8
• Primaquine reduces relapse risk by 80% in P. vivax malaria 1

Common Adverse Events

• Gastrointestinal symptoms (mild) 8
• Methemoglobinemia (usually asymptomatic) 1
• Hemolysis in G6PD-deficient patients 3, 1

Critical Pitfalls to Avoid

Never Skip G6PD Testing

• Administering primaquine without knowing G6PD status risks severe hemolytic anemia and death 3, 1
• If G6PD testing is unavailable, use the weekly dosing regimen (0.75 mg/kg once weekly for 8 weeks) which is safer in unscreened populations 3, 1

Never Give Primaquine During Pregnancy

• Primaquine is contraindicated in pregnancy and must be deferred until after delivery 1
• Always perform pregnancy screening before prescribing 1

Do Not Use Low-Dose Regimens in Southeast Asia

• The 0.25 mg/kg/day dose is inadequate for Southeast Asian strains 1, 4
• Policy makers in Southeast Asia should endorse the 7.0 mg/kg total dose regimen 4

Monitor G6PD Heterozygous Females Closely

• Female heterozygotes can experience significant hemolysis requiring transfusion 7
• Consider quantitative point-of-care G6PD testing before using high-dose regimens 7