What is the appropriate initial management for a patient who develops jaundice while taking primaquine, including the necessary work‑up and alternative malaria prophylaxis?

Management of Primaquine-Induced Jaundice

Stop primaquine immediately and test for G6PD deficiency, as jaundice in this context most likely represents hemolytic anemia from underlying G6PD deficiency rather than hepatotoxicity. 1

Immediate Actions

• Discontinue primaquine promptly upon recognition of jaundice, darkening of urine, or marked fall in hemoglobin or erythrocyte count, as these are signs of hemolytic anemia 1
• Obtain urgent laboratory work-up including:
  • Complete blood count with hemoglobin, hematocrit, and reticulocyte count 1
  • G6PD enzyme activity testing (quantitative assay) 1
  • Peripheral blood smear looking for hemolysis (schistocytes, spherocytes) 2
  • Total and direct bilirubin to confirm hemolytic pattern (elevated indirect bilirubin) 2
  • Lactate dehydrogenase and haptoglobin 2
  • Urinalysis for hemoglobinuria 1
  • Renal function tests (creatinine, BUN) as primaquine-induced hemolysis can cause renal tubular injury 2

Understanding the Mechanism

• Primaquine causes hemolytic reactions (moderate to severe) in individuals with G6PD deficiency, particularly those from Africa, Southern Europe, Mediterranean region, Middle East, South-East Asia, and Oceania where G6PD deficiency prevalence is high 1
• The Mediterranean G6PD variant (B-) carries very high risk of severe complications with primaquine 3
• Jaundice develops from hemolysis-induced hyperbilirubinemia, not hepatocellular injury 2, 4

Supportive Management

• Ensure adequate hydration to protect renal function from hemoglobin precipitation in renal tubules 2
• Monitor hemoglobin closely; transfuse packed red blood cells if hemoglobin drops below 7 g/dL or patient becomes symptomatic 5
• Acetaminophen/paracetamol is safe for symptomatic relief even during severe oxidative hemolysis 2
• Do not administer methylene blue if G6PD deficiency is confirmed or suspected, as it may worsen hemolytic anemia in G6PD-deficient patients 5

Completing Malaria Treatment

• Continue chloroquine (or alternative blood-stage antimalarial) to complete treatment of the acute infection, with chloroquine at 1000 mg salt initially, then 500 mg at 6,24, and 48 hours for P. vivax 3
• Alternative blood-stage treatments include artemether-lumefantrine or dihydroartemisinin-piperaquine if chloroquine resistance is suspected 3
• These blood-stage antimalarials do not cause hemolysis and can be safely continued 3

Alternative Strategies for Radical Cure

Once the patient stabilizes and G6PD status is confirmed:

For Patients with Severe G6PD Deficiency (<30% activity):

• Primaquine is absolutely contraindicated 6
• Consider treating relapses as they occur rather than attempting radical cure, which is a reasonable strategy in non-endemic settings where reinfection risk is absent 3
• This approach prioritizes patient safety over theoretical relapse prevention 3

For Patients with Intermediate G6PD Deficiency (30-70% activity):

• Once methemoglobin and hemoglobin normalize, consider weekly primaquine at 0.75 mg base/kg (maximum 45 mg) for 8 weeks with close monitoring 3
• Requires weekly hemoglobin and methemoglobin monitoring throughout treatment 3
• This modified regimen reduces hemolysis risk while still providing radical cure 7

For Patients with Normal or Near-Normal G6PD Activity (>70%):

• Standard 14-day primaquine regimen (15 mg base daily) can be attempted after full recovery 8, 6
• Close hematological monitoring at days 3 and 8 is required 1

Alternative Medication:

• Tafenoquine 300 mg single dose may be considered as an alternative (only available in United States and Australia, not Europe), but requires quantitative G6PD testing showing >70% activity 3

Critical Caveats

• In populations where severe G6PD deficiency is common (notably among Asians), primaquine should not be administered for greater than 5 days due to risk of life-threatening hemolysis 8
• G6PD testing should have been performed before initiating primaquine; this case represents a failure of pre-treatment screening 1
• Pregnant women, breastfeeding women, and infants less than 6 months old should never receive primaquine regardless of G6PD status 1
• Acute hemolysis transiently increases measured G6PD activity, so retesting should be delayed until at least 3 months after the hemolytic episode to obtain accurate baseline G6PD status 2