Primaquine

Primaquine is an antimalarial medicine approved for use in the following situation:

• Radical cure of vivax malaria: Primaquine Phosphate Tablets eliminate the dormant liver-stage parasites (P. vivax hypnozoites) that cause the infection to relapse.
• Prevention of relapse in vivax malaria: Primaquine Phosphate Tablets are taken alongside or after chloroquine to prevent the infection from returning.
• After chloroquine suppressive therapy: Primaquine Phosphate Tablets are used following the end of chloroquine prevention in areas where vivax malaria is endemic.

Primaquine belongs to a class of antimalarials called 8-aminoquinolines. It specifically targets the dormant liver-stage parasites of P. vivax — called hypnozoites — that standard antimalarials can't reach. It's thought to work by interfering with the parasite's energy-producing system (mitochondria) and by generating damaging reactive compounds inside infected cells. The drug is converted in the liver by an enzyme called CYP2D6 into active forms that do the work; people whose CYP2D6 enzyme is less active (known as poor or intermediate metabolizers) may not convert primaquine as effectively, which could reduce how well it works.

Primaquine is also active against gametocytes — the reproductive stage of Plasmodium falciparum — though this use is not what it is formally approved for.

Primaquine Phosphate Tablets are taken by mouth once daily for 14 days. They can be taken with or without food, though food (particularly a fatty meal) may increase the amount of drug absorbed and may reduce stomach upset. Primaquine is typically given at the same time as a course of chloroquine, which quickly clears the active blood-stage infection while primaquine works on the liver-stage parasites.

• Take exactly as prescribed — do not skip doses or stop early
• If you miss a dose, follow your pharmacist's or prescriber's advice — do not double up without guidance
• Blood tests (hemoglobin and hematocrit) are needed before and during treatment

The most common side effects of primaquine involve the stomach and the blood:

• Nausea and vomiting
• Stomach cramps and upper abdominal discomfort
• Decreased hemoglobin (lower red blood cell oxygen-carrying capacity)
• Methemoglobinemia (a blood disorder where cells carry less oxygen, sometimes causing a bluish skin color)
• Low white blood cell count (leukopenia)
• Hemolytic anemia — red blood cell breakdown, especially in G6PD-deficient individuals

Hemolytic anemia can be severe or life-threatening in people with severe G6PD deficiency. Dark urine, pale skin, dizziness, or unusual shortness of breath are warning signs to act on immediately — stop the medicine and call your doctor or seek emergency care.

• G6PD deficiency and hemolytic anemia: This is the most serious risk. A G6PD test must be done before starting treatment. Severe G6PD deficiency means primaquine cannot be used. Even in mild-to-moderate deficiency, careful monitoring is required. People of African, Mediterranean, Middle Eastern, South-East Asian, and Oceanian backgrounds are at higher risk.
• Pregnancy: Primaquine is contraindicated in pregnant women. It can harm a fetus that is G6PD deficient, even if the mother has normal G6PD. A pregnancy test is required before starting in women who could become pregnant.
• Breastfeeding: Primaquine should not be used by breastfeeding mothers if the infant's G6PD status is unknown or if the infant is G6PD deficient.
• Contraception requirements: Women should use effective contraception during treatment and until two menstrual cycles pass after stopping. Men whose partners could become pregnant should use condoms during treatment and for 3 months after.
• Drug interactions: Combining primaquine with quinacrine, other hemolytic drugs, or methemoglobinemia-causing medicines is dangerous and should be avoided.
• Blood monitoring: Routine blood counts and hemoglobin checks are advised for all patients during treatment.

Primaquine interacts with a number of medicines that can either make it more dangerous or affect how well it works:

• Quinacrine (mepacrine): Contraindicated — this combination greatly increases toxicity
• Hemolytic agents: Any drug that can also break down red blood cells should be avoided — the risk of serious anemia compounds
• Methemoglobinemia-inducing drugs: Avoid concurrent use; close blood monitoring is needed if unavoidable
• QT-prolonging drugs: Primaquine may affect heart rhythm; combining with other QT-prolonging medicines requires frequent heart monitoring (ECG)
• Strong CYP2D6 inhibitors: May reduce primaquine's antimalarial effectiveness by blocking its conversion to active forms — consider alternatives
• MAO-A inhibitors: In people who are poor/intermediate CYP2D6 metabolizers, adding an MAO-A inhibitor can raise primaquine levels significantly, increasing adverse effect risk
• CYP1A2 substrates (e.g., duloxetine, theophylline, tizanidine): Primaquine may raise their blood levels — monitor for increased side effects of those medicines
• CYP3A4 and P-gp substrates (e.g., digoxin, dabigatran, rivaroxaban, pimozide): Primaquine may increase concentrations of these drugs — check the prescribing information for each

This is not a complete list of interactions. Always talk with your doctor or pharmacist before starting, stopping, or changing any medication.

• G6PD deficiency: Must be tested before starting — severe G6PD deficiency is a contraindication; mild-to-moderate requires careful monitoring
• Pregnancy: Primaquine is contraindicated — do not take if pregnant; effective contraception is required
• Breastfeeding: Avoid if infant's G6PD status is unknown or if infant is G6PD deficient
• Personal or family history of hemolytic anemia or favism: Tell your doctor — you are at higher risk
• Rheumatoid arthritis or lupus erythematosus: Primaquine is contraindicated in patients who are acutely ill with these conditions
• Currently taking hemolytic drugs or bone marrow-suppressing medicines: Primaquine is contraindicated in combination
• Liver disease: Moderate hepatic impairment affects how primaquine is processed; risk of metabolite accumulation with repeated dosing is unknown
• Severe kidney disease: Higher drug levels have been seen — accumulation of metabolites with repeated dosing is a potential concern
• Older adults (over 52 years): No pharmacokinetic data are available in this age group; discuss with your prescriber
• CYP2D6 poor or intermediate metabolizers: Primaquine may be less effective in people whose CYP2D6 enzyme is less active; discuss genetic testing with your doctor if relevant

Taking too much primaquine can cause severe stomach cramps, vomiting, headache, insomnia, methemoglobinemia (bluish skin from low blood oxygen), dangerous heart rhythm changes (including QT prolongation), low white blood cell counts, and serious hemolytic anemia — especially dangerous in people with G6PD deficiency. If overdose is suspected, contact a poison control center or seek emergency medical care immediately.

Primaquine works directly on the liver-stage (exoerythrocytic) forms of P. vivax, including the dormant hypnozoites responsible for malaria relapses. By eliminating these forms, it prevents the parasite from re-entering the bloodstream and causing another active infection. It is also active against Plasmodium falciparum gametocytes — the stage that can be transmitted to mosquitoes. In susceptible individuals, primaquine's metabolites can cause oxidative damage to red blood cells, which is the basis for the hemolytic anemia risk in G6PD-deficient patients.

After an oral dose, primaquine is well absorbed (over 70% bioavailability) and reaches peak blood levels in about 2 to 3 hours. Eating a fatty meal increases how much drug gets into the bloodstream. Primaquine is primarily processed in the liver — by the CYP2D6 and MAO-A enzymes — into metabolites, and the drug has a relatively short half-life of about 5 to 6 hours. About 64% of the dose is eventually excreted in the urine as metabolites. People with reduced or absent CYP2D6 enzyme activity (poor or intermediate metabolizers) may have altered drug levels and reduced formation of the active metabolites thought to be responsible for primaquine's antimalarial effect.

Store at 25° C (77° F); excursions permitted to 15° C – 30° C (59° F – 86° F) Dispense in tight, light-resistant container as defined in the USP/NF.