Primaquine Phosphate

A. Approved Indications

• Radical cure of Plasmodium vivax and Plasmodium ovale malaria:
  To eliminate hepatic hypnozoites and prevent relapse after treatment with blood-stage antimalarials (e.g., chloroquine).
• Gametocytocidal therapy in Plasmodium falciparum malaria:
  Single-dose therapy to block transmission of P. falciparum by killing mature gametocytes.
• Prophylaxis of malaria:
  In select individuals traveling to areas with high P. vivax or P. ovale transmission (less commonly used today).

B. Clinically Accepted Off-Label Uses

• Treatment of Pneumocystis jirovecii pneumonia (PCP):
  Used in combination with clindamycin in patients intolerant to trimethoprim-sulfamethoxazole.
• Relapse prevention in mixed infections:
  As part of combination regimens for P. vivax/P. falciparum coinfections.

Route: Oral only

Take with food to reduce gastrointestinal side effects.

Adults:

• Radical cure (P. vivax or P. ovale):
  15 mg (base) once daily for 14 days (total dose: 210 mg base)
  In some regions, 30 mg daily for 14 days is used to improve efficacy
• P. falciparum gametocytocidal dose:
  Single dose of 45 mg (base) orally
• PCP (with clindamycin):
  15–30 mg (base) orally once daily for 21 days (adjust per protocol)

Children:

• Radical cure:
  0.25–0.5 mg/kg (base) once daily for 14 days (max: adult dose)
  Always verify G6PD status prior to use

Elderly:

• Same as adult dosage; monitor closely for hemolysis and hepatic function

Renal Impairment:

• Use with caution; limited data on dose adjustment
• Monitor for signs of hemolysis, especially if G6PD deficiency is suspected

Hepatic Impairment:

• Caution advised; metabolism occurs in liver
• No specific dose recommendations, but monitor for toxicity

G6PD Screening Required Before Use:

• Primaquine may cause severe hemolysis in patients with G6PD deficiency
• Confirm normal G6PD activity prior to initiation

Primaquine is an 8-aminoquinoline antimalarial that exerts its effect by generating reactive oxygen species (ROS) and interfering with the parasite’s mitochondrial electron transport chain. It is especially active against exo-erythrocytic hepatic forms (hypnozoites) of P. vivax and P. ovale, as well as gametocytes of P. falciparum. The generation of ROS and inhibition of mitochondrial function disrupt parasite replication and survival, leading to complete eradication of latent liver forms and prevention of malaria relapse or transmission.

• Absorption:
  Rapidly absorbed after oral administration; peak plasma concentration in 1–3 hours
• Bioavailability:
  Approximately 96%; food may enhance gastrointestinal tolerance
• Distribution:
  Widely distributed in body tissues; concentrates in liver, spleen, and lungs
  Moderate plasma protein binding
• Metabolism:
  Extensively metabolized in the liver via CYP enzymes (mainly CYP2D6) into active and potentially hemolytic metabolites
• Half-life:
  4 to 6 hours (varies with metabolic capacity)
• Elimination:
  Primarily renal excretion as inactive metabolites
  <5% excreted unchanged

• Pregnancy:
  FDA Pregnancy Category D
  Contraindicated in pregnancy due to potential risk of hemolytic anemia in the fetus (fetal G6PD status unknown). Delay therapy until after delivery if possible.
• Lactation:
  Contraindicated during breastfeeding unless the infant is known to be G6PD normal, due to risk of hemolytic anemia from drug excretion in breast milk.

• Primary Class: Antimalarial Agent
• Subclass: 8-Aminoquinoline Derivative
• Additional Role: Antiprotozoal (PCP adjunctive therapy)

• Known hypersensitivity to primaquine or related compounds
• G6PD deficiency (absolute contraindication)
• Pregnancy (unless no alternatives available and benefits outweigh risks)
• Breastfeeding when infant's G6PD status is unknown or deficient
• Severe hepatic or renal disease (use with caution or avoid)
• History of methemoglobinemia or hemolytic anemia

• Hemolysis in G6PD deficiency:
  Can cause life-threatening hemolysis. Always screen for G6PD prior to use.
• Methemoglobinemia:
  Monitor patients for cyanosis, fatigue, or altered oxygen saturation. More likely in neonates and those with NADH-methemoglobin reductase deficiency.
• CYP2D6 Polymorphism:
  Poor metabolizers may have reduced drug efficacy against P. vivax.
• Caution in anemia or hematologic disorders:
  May worsen existing anemia or cause severe hemolytic episodes.
• Drug-induced hepatitis:
  Monitor liver enzymes in long-term or repeated courses.
• Avoid alcohol:
  Alcohol may worsen gastrointestinal effects.

Common:

• Gastrointestinal:
  Nausea, vomiting, abdominal pain, epigastric discomfort
  (minimized when taken with food)
• Hematologic:
  Mild hemolysis (even in G6PD-normal individuals at higher doses)
• Neurological:
  Headache, dizziness

Serious/Rare:

• Severe hemolytic anemia (especially in G6PD deficiency)
• Methemoglobinemia
• Leukopenia
• Hepatotoxicity
• Allergic skin reactions (rash, pruritus)

Adverse effects are dose-related and more severe in predisposed individuals.

• Other hemolytic drugs (e.g., dapsone, sulfonamides):
  Increased risk of oxidative stress and hemolysis
• CYP2D6 inhibitors (e.g., fluoxetine, paroxetine, quinidine):
  May reduce conversion to active metabolites and decrease efficacy
• Drugs causing methemoglobinemia (e.g., nitrates, phenazopyridine):
  Additive risk for cyanosis or hypoxia
• Chloroquine/Quinine:
  Often used concurrently; no known pharmacokinetic interactions
• Alcohol:
  May exacerbate gastrointestinal irritation

• WHO Malaria Treatment Guidelines (latest edition):
  Recommend high-dose primaquine (0.5 mg/kg/day for 14 days) in areas with chloroquine resistance or P. vivax relapse
• CDC Updates:
  Reiterate the importance of G6PD testing before prescribing and highlight concerns with CYP2D6 variability
• EMA/FDA Communications:
  Safety labels include warnings for methemoglobinemia and reinforce strict G6PD screening prior to therapy

• Temperature: Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C–30°C
• Humidity/Light: Store in a dry place, protected from light and moisture
• Handling: Keep tightly closed in original container
• Reconstitution/Refrigeration: Not applicable
• Shelf Life: Refer to manufacturer’s label; do not use beyond expiry date