Primaquine

Primaquine (or primaquine phosphate) is a medication used in the treatment of malaria and Pneumocystis pneumonia. It is a member of the 8-aminoquinoline group of drugs that includes pamaquine.

Additional recommended knowledge

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Indications

Radical cure

Primaquine is mainly used to treat the P. vivax or P. ovale malaria. Once the parasite has been eliminated from the bloodstream, the remaining hypnozoites must be removed from the liver and this is done by administering a 14 day course of primaquine (called radical cure).

If primaquine is not administered to patients with proven P. vivax or P. ovale infection, there is a very high likelihood relapse within weeks or months (sometimes years).

When attempting a radical cure, primaquine requires the presence of quinine or chloroquine in order to work.^[2] If primaquine is given alone, the cure rate is only 21%. This is why primaquine should always be given with quinine or chloroquine. It is not known if other antimalarials such as mefloquine are likewise able to potentiate the effect of primaquine.

Primary prophylaxis

Primaquine is not routinely used to prevent malaria in travellers, and is only used as such when no other alternatives are appropriate.^[3] It is not licensed for this use in the U.S. or UK.

Terminal prophylaxis

Primaquine is also sometimes used presumptively to prevent malaria in people who have gone to areas where P. vivax or P. ovale are endemic (called terminal prophylaxis), but this practise is not common outside of the U.S. and is controversial.

Pneumocystis pneumonia

Primaquine is also used in the treatment of Pneumocystis pneumonia, a fungal infection commonly occurring in people with AIDS and, more rarely, in those taking immunosuppressive drugs. To treat PCP effectively it is usually combined with clindamycin.

Adverse reactions

Side effects of primaquine administration include nausea, vomiting, and stomach cramps. Other known adverse effects that occasionally occur are headache, visual disturbances and intense itching. Primaquine has also been shown to cause Hemolytic anemia in people of African or Mediterranean descent.

Primaquine causes methemoglobinemia in all patients who take it (levels of up to 18% are reported, normal level is <1%), but this seldom causes symptoms and is always self-limiting.^[4] Dangerous levels of methemoglobinemia only occur in patients with glucose-6-phosphate dehydrogenase deficiency.^[5][6]

Contraindications

Primaquine should not be administered to anyone with Glucose-6-phosphate dehydrogenase deficiency as there can be a severe reaction with hemolytic anemia. Primaquine is contraindicated in pregnancy, because the G-6-PD status of the fetus will not be unknown. Primaquine should not be given to patients with NADH methemoglobin reductase deficiency.^[5][6]

The packaging label states that primaqine should not be given to patients with systemic lupus erythematosus or rheumatoid arthritis, but the rationale behind this is questionable.^[3]

Dosing

Primaquine doses are always expressed as base, not as salt (15 mg base=26.3 mg phosphate salt).

Radical cure

• Plasmodium vivax: 30 mg once daily for 14 days^[7] (note that older authorities quote 15 mg instead);
• Plasmodium ovale: 15 mg once daily for 14 days.

The FDA licensed dose in the U.S. is 15 mg once daily, but this is not the dose recommended by the CDC for P. vivax; the FDA decision in 1952 to limit the primaquine dose to 15 mg was motivated by the fact that G-6-PD testing was not routinely available, 15 mg was known to be effective against the P. vivax strains found in Korea (in the US, the main use of primaquine at that time was to treat soldiers returning from war), and because 15 mg of primaquine is not likely to cause hemolysis in G-6-PD deficient patients.^[3] Primaquine is not licensed in the UK, but is available on a named-patient basis.

Primary prophylaxis

The dose of primaquine in primary malaria prophylaxis is 30 mg once daily, starting the day before travel and continuing for 7 days after returning. It needs only to be given for seven days after returning because primaquine is active against liver schizonts (the exoerythrocytic stages) and is therefore a causal prophylactic. In children, the dose is 0.6 mg/kg/day (the maximum daily dose is 30 mg).

Manufacturing and availability

Primaquine was first tested on humans during the Stateville Penitentiary Malaria Study in 1944. Primaquine was licensed for use in the US by the FDA in 1952 and is available as a generic drug from a variety of manufacturers.

Primaquine is not licensed for use in the UK. It is available on a named patient basis only from Durbin or IDIS. Primaquine tablets available in the UK contain 7.5 mg primaquine base (13.2 mg phosphate salt). Primaquine tablets available in the U.S. contain 15 mg base (26.3 mg phosphate salt).

References

1. ^ Mihaly GW, Ward SA, Edwards G, et al. (1985). "Pharmacokinetics of primaquine in man. I. studies of the absolute bioavailability and effects of dose size". Br J Clin Pharmacol 19: 745–50. PMID 4027117.
2. ^ Alving AS, Arnold J, Hockwald RS, et al. (1955). "Potentiation of the curative action of primaquine in vivax malaria by quinine and chloroquine". J Lab Clin Med 46: 301–6. PMID 13242948.
3. ^ ^{a b c} Hill DR, Baird JK, Parise ME, et al. (2006). "Primaquine: Report from CDC expert meeting on malaria chemoprophylaxis I". Am J Trop Med Hyg 75 (3): 402–15. PMID 16968913.
4. ^ Clayman CB, Arnold J, Hockwold RS, et al. (1952). "Toxicity of primaquine in caucasians". JAMA 149: 1563–68.
5. ^ ^{a b} Cohen RJ, Sachs JR, Wicker DJ, Conrad ME. (1968). "Methemoglobinemia provoked by malarial chemoprophylaxis in Vietnam". N Engl J Med 279: 1127–31. PMID 5686480.
6. ^ ^{a b} Coleman MD, Coleman NA. (1996). "Drug-induced methaemoglobinaemia. Treatment issues". Drug Saf 14: 394–405. PMID 8828017.
7. ^ Baird JK, Hoffman SL. (2004). "Primaquine therapy for malaria". Clin Infect Dis 39: 1336–45. PMID 15494911.

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