Primaquine phosphate is an 8-aminoquinoline antimalarial agent with a distinct and critical role in modern parasitology. It is the only widely available medication indicated for the radical cure of Plasmodium vivax and Plasmodium ovale malaria, targeting the dormant hypnozoite forms that reside in the liver and cause relapsing infections. Its use is a cornerstone of malaria control and elimination strategies, preventing the long-term morbidity associated with recurrent parasitemia. This expert guide details the pharmacology, clinical application, and essential safety considerations for this potent therapeutic.

Features

• Active Pharmaceutical Ingredient: Primaquine phosphate (equivalent to primaquine base).
• Pharmacological Class: 8-Aminoqunoline antimalarial.
• Primary Mechanism of Action: Generates reactive oxygen species that interfere with the mitochondrial electron transport chain in Plasmodium species.
• Key Indication: Radical cure (elimination of hypnozoites) of P. vivax and P. ovale malaria.
• Secondary Indication: Prophylaxis against all species of malaria (in specific scenarios).
• Additional Indication: Primary treatment for P. vivax malaria when combined with a blood schizonticide like chloroquine.
• Formulations: Typically available as 7.5 mg and 15 mg base equivalent tablets.

Benefits

• Achieves a radical cure by eradicating the dormant liver-stage hypnozoites of P. vivax and P. ovale, preventing relapses that can occur months or even years after the initial infection.
• Significantly reduces the reservoir of transmissible infection within a population, a critical component of public health efforts aimed at malaria elimination.
• Provides causal prophylaxis by targeting the pre-erythrocytic (liver stage) forms of all malaria parasite species, preventing the onset of clinical disease.
• Reduces long-term morbidity, healthcare costs, and mortality associated with repeated episodes of malarial illness.
• Gametocytocidal activity against Plasmodium falciparum, reducing the transmissibility of the parasite and helping to interrupt the cycle of infection.

Common use

Primaquine is exclusively prescribed for the prevention and treatment of malaria. Its most vital application is for the “radical cure” of relapsing malaria caused by P. vivax and P. ovale. This involves a standard 14-day course following initial treatment with a fast-acting blood schizonticide (e.g., chloroquine or artemisinin-based combination therapy) to clear the acute blood-stage infection. It is also used for terminal prophylaxis in individuals with significant exposure to these relapsing species, administered towards the end of or after leaving an endemic area. In rare cases, it may be used for primary prophylaxis against all malarial species in specific circumstances, though this is not a first-line recommendation due to the risk of hemolysis. For P. falciparum, a single low dose is used as a gametocytocide to reduce transmission in mass drug administration campaigns, a key strategy in elimination programs.

Dosage and direction

Dosing is always calculated based on the primaquine base (not the salt). Adherence to the full course is paramount for efficacy.

• Radical Cure for P. vivax and P. ovale Malaria: The standard regimen is 0.5 mg base/kg (or 30 mg base for adults) orally once daily for 14 days. This is initiated concurrently with or immediately following the blood schizontocide.
• Terminal Prophylaxis: 0.5 mg base/kg (or 30 mg base for adults) orally once daily for 14 days after leaving the endemic area.
• Primary Prophylaxis (alternative regimen): 0.5 mg base/kg (or 30 mg base for adults) orally once daily, starting 1-2 days before travel to an endemic area, continued daily while in the area, and for 7 days after leaving.
• Gametocytocidal Dose for P. falciparum: A single dose of 0.75 mg base/kg (or 45 mg base for adults) is administered, typically as part of a public health intervention.

CRITICAL NOTE: All patients must be tested for Glucose-6-Phosphate Dehydrogenase (G6PD) deficiency prior to initiation. Dosage adjustments or alternative therapies are required for G6PD-deficient individuals.

Precautions

• G6PD Testing is Mandatory: The most significant precaution is the absolute requirement to quantify G6PD enzyme activity before prescribing. Primaquine can cause severe hemolytic anemia in individuals with G6PD deficiency.
• Pregnancy: Contraindicated during pregnancy due to the unknown G6PD status of the fetus and the risk of fetal hemolysis. Use only if the potential benefit justifies the potential risk to the fetus.
• Lactation: Should generally be avoided in breastfeeding women unless the infant has been confirmed to have normal G6PD activity.
• Nicotinamide Adenine Dinucleotide (NADH) Methemoglobin Reductase Deficiency: Individuals with this deficiency are at an increased risk of developing methemoglobinemia.
• Monitoring: Patients should be advised to monitor for signs of hemolysis (e.g., dark urine, jaundice, fatigue, shortness of breath) and to seek immediate medical attention if they occur.

Contraindications

• Confirmed or suspected G6PD deficiency (absolute contraindication for standard dosing).
• Pregnancy.
• Breastfeeding by an infant with unknown or known G6PD deficiency.
• Known hypersensitivity to primaquine or any component of the formulation.
• Concomitant use with other agents known to cause hemolysis or depress the myeloid elements of the bone marrow.
• Active rheumatoid arthritis or lupus erythematosus (may be exacerbated).

Possible side effect

• Common: Abdominal cramps, nausea, vomiting, epigastric distress, chest pain, weakness. These are often dose-related and manageable.
• Serious:
  • Hemolytic Anemia: The most serious adverse reaction, occurring primarily in individuals with G6PD deficiency. Presents with fatigue, tachycardia, pallor, jaundice, and dark-colored urine (hemoglobinuria).
  • Methemoglobinemia: Can occur even in individuals with normal G6PD activity, presenting as cyanosis (bluish discoloration of skin), headache, dizziness, fatigue, and shortness of breath.
  • Leukopenia: A decrease in white blood cell count.
  • Agranulocytosis: A severe, acute drop in granulocyte count.
  • Cardiac Arrhythmias: Rare.

Drug interaction

• Other Hemolytic Drugs: Concurrent use with drugs like sulfonamides, dapsone, nitrofurantoin, or quinine may increase the risk of hemolytic reactions.
• Myelosuppressive Agents: Drugs that suppress bone marrow function (e.g., chemotherapy, some antivirals) may compound the risk of leukopenia or agranulocytosis.
• Drugs Causing Methemoglobinemia: Concurrent use with local anesthetics (e.g., benzocaine), nitrates, or dapsone may increase the risk of methemoglobinemia.

Missed dose

If a dose is missed, it should be taken as soon as it is remembered. However, if it is almost time for the next scheduled dose, the missed dose should be skipped. The patient should not double the dose to make up for the missed one. Maintaining the prescribed daily schedule is critical for the 14-day radical cure regimen to be effective.

Overdose

Symptoms of overdose are an exaggeration of its known adverse effects: severe abdominal cramps, vomiting, burning epigastric distress, central nervous and cardiovascular disturbances, cyanosis (from methemoglobinemia), methemoglobinemia, granulocytopenia, and acute hemolytic anemia in susceptible individuals. There is no specific antidote. Management is supportive and includes gastric lavage (if ingestion was recent), monitoring of vital signs, hematologic parameters, and methemoglobin levels. Severe hemolysis may require transfusions. Severe methemoglobinemia may be treated with methylene blue; however, methylene blue is itself contraindicated in G6PD-deficient patients as it can cause hemolysis, so the patient’s G6PD status must be known before administration.

Storage

Store at controlled room temperature, 20°C to 25°C (68°F to 77°F). Excursions are permitted between 15°C and 30°C (59°F and 86°F). Keep the container tightly closed and protect from light and moisture. Keep out of reach of children and pets.

Disclaimer

This information is for educational and informational purposes only and does not constitute medical advice. It is not a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of a qualified physician or other licensed health provider with any questions you may have regarding a medical condition or before starting any new treatment. Never disregard professional medical advice or delay in seeking it because of something you have read here. The author and publisher are not responsible for any errors or omissions or for any consequences from the application of this information.

Reviews

• “As an infectious disease specialist working in Southeast Asia, primaquine is an indispensable tool. The 14-day course for radical cure of P. vivax has dramatically reduced the rate of relapse in our patient population. The mandatory G6PD screening is a non-negotiable part of our protocol.” – Dr. A. Sharma, MD
• “From a public health perspective, the gametocytocidal activity of primaquine is a game-changer for falciparum elimination campaigns. The single low dose is well-tolerated and crucial for reducing transmission.” – Public Health Officer, Regional Malaria Program
• “The patient education component is critical. We spend considerable time ensuring patients understand the importance of completing the full 14-day regimen and recognizing the signs of potential hemolysis. This vigilance makes the therapy both safe and effective.” – Clinical Pharmacist
• “While the side effect profile requires respect and careful management, the benefit of preventing debilitating relapses makes primaquine a cornerstone of antimalarial therapy. It remains the gold standard for which we have no equivalent replacement.” – Tropical Medicine Researcher