What are the side effects and contraindications of Primaquine (antimalarial medication)?

Primaquine Side Effects and Contraindications

Primaquine is absolutely contraindicated in patients with severe G6PD deficiency due to the risk of potentially life-threatening hemolytic anemia, and G6PD testing must be performed before initiating treatment. 1

Major Side Effects

Hematologic Effects

• Hemolytic anemia: Most serious adverse effect, particularly in G6PD-deficient individuals 1, 2
• Methemoglobinemia: Can occur even in patients with normal G6PD status 3

Gastrointestinal Effects

• Nausea and vomiting 3
• Diarrhea 3
• Abdominal discomfort

Other Side Effects

• Skin rashes 3
• Elevated liver enzymes 3
• Renal tubular injury (evidenced by elevated urinary beta-2-microglobulin) during acute hemolysis 2
• Glomerular glycocalyx degradation during severe hemolysis 2

Absolute Contraindications

• Severe G6PD deficiency 1
• Pregnancy: The drug may be passed transplacentally to a G6PD-deficient fetus and cause hemolytic anemia in utero 3, 1
• Concurrent use with other hemolytic drugs 1
• Concurrent use with quinacrine (potentiates toxicity) 1
• Acute systemic diseases with tendency to granulocytopenia (e.g., rheumatoid arthritis, lupus erythematosus) 1

Relative Contraindications/Precautions

• Mild to moderate G6PD deficiency: Decision to use primaquine must be based on risk-benefit assessment with close hematological monitoring 1
• Breastfeeding: It's not known whether primaquine is excreted in human milk; decision should consider importance of drug to mother 1
• Unknown G6PD status: When G6PD testing is unavailable, careful risk assessment is needed with baseline hematological testing and close monitoring 1, 4

Special Populations

Women of Reproductive Potential

• Pregnancy testing prior to starting treatment 1
• Effective contraception during treatment and until completion of an ongoing ovulatory cycle 1
• Male partners should use condoms during treatment and for 3 months after stopping primaquine 1

Children

• Dosing adjustments required based on weight 3
• Safety profile similar to adults when properly dosed 3

Monitoring Requirements

1. Pre-treatment:

   • G6PD testing (mandatory) 1, 5
   • Baseline hematocrit and hemoglobin 1
   • Pregnancy test for women of reproductive potential 1

2. During treatment:

   • Close hematological monitoring, especially on days 3 and 8 1
   • Monitor for signs of hemolysis (darkening of urine, fatigue, pallor) 1
   • Discontinue immediately if signs of hemolytic anemia occur 1

Alternative Dosing Strategies for G6PD-Deficient Patients

• For patients with mild to moderate G6PD deficiency (non-Mediterranean variants), weekly dosing regimen (0.75 mg/kg once weekly for 8 weeks) may be safer than daily dosing 4, 6
• Recent research suggests ascending dose regimens may be tolerated in certain G6PD-deficient populations, potentially allowing for shorter treatment courses compared to the 8-week regimen 7

Clinical Pearls

• The risk of hemolysis varies with different G6PD variants; Mediterranean variants (B-) have higher risk of severe hemolysis than African variants (A-) 3
• G6PD testing has limitations and may not detect all heterozygous females at risk 4
• Primaquine-induced hemolysis can transiently increase measured G6PD activity during acute episodes 2
• For P. vivax radical cure, a 7-day regimen (0.5 mg/kg/day) may be as effective as the standard 14-day course with similar safety profile in G6PD-normal patients 8

Remember that while primaquine is essential for preventing P. vivax and P. ovale relapses, its underuse due to concerns about G6PD deficiency remains a significant barrier to effective malaria control in endemic regions 4, 6.