It is not necessary to provide antirelapse treatment routinely to patients living in endemic areas with unabated transmission. In such cases, a relapse cannot be distinguished from reinfection and such patients should be treated with an effective blood schizonticide for each symptomatic recurrence of parasitaemia.

In areas with seasonal transmission where relapses occur 6-12 months after the primary attack, antirelapse treatment with primaquine can be delayed. This provides an operational advantage in programmes aimed at interrupting transmission since all persons at risk can be treated (mass drug administration) at the end of the transmission season. This will save time and will also catch reinfections in patients who have already been treated. Pregnant patients in whom primaquine is contraindicated, should be treated only after delivery.

As a gametocytocidal drug in P. falciparum infections.

Gametocytocidal treatment is given only for falciparum malaria in areas with low or moderate malaria transmission. Its objective is the elimination of residual gametocytes after effective blood schizonticidal treatment. For this purpose, a single dose of 0.75 mg/kg is used.

Recommended treatment

Antirelapse treatment in P. vivax and P. ovale infections.

Primaquine may be given concurrently with an active blood schizonticide, such as chloroquine, from the first day of treatment. There are geographical variations in the susceptibility of P. vivax to primaquine used for antirelapse therapy (see above).

Antirelapse treatment of vivax malaria with primaquine at doses of 0.5 mg/kg for 14 days has been recommended for South-East Asia and Western Pacific countries. This dose level should only apply to areas south of the equator (where the Chesson strain of P. vivax occurs). In areas north of the equator, treatment with 0.25 mg/kg for 14 days is sufficient.

It should be noted that the previously recommended 5-day treatment with primaquine was derived largely on the basis of empirical views. The dose of 15 mg/kg given for 5 days exerts little or no antirelapse activity (70, 288, 289).

When possible, G6PD deficiency should be excluded before standard therapeutic doses of primaquine are given as antirelapse therapy. Relatively simple and inexpensive qualitative kits are now available for this purpose. About 10% of black Africans have a mild, self-limited haemolysis with a dosage of 15 mg of base per kg for 14 days. In persons of Mediterranean or Asian origin with a rarer form of G6PD deficiency, a severe, life-threatening haemolysis can occur (290). In patients with the milder form of G6PD deficiency, an intermittent treatment regimen of 0.75 mg of base per kg weekly for 8 weeks may be administered under medical supervision to reduce the risk of haemolysis (291). Patients should be warned to stop treatment and seek medical advice if they have abdominal pain, become weak or pale, or notice darkening of the urine.

Adherence to these antirelapse regimens is often poor. Ideally, the drug should be given under supervision, but this creates enormous operational difficulties for malaria control programmes.

Gametocytocidal drug in P. falciparum infections.

Single dose of 0.75 mg of base per kg base (adults; 45 mg of base); the same dose may be repeated once, one week later.

Gametocytocidal treatment should only be given in association with or following effective blood schizonticidal medication. Primaquine may be given concurrently with the schizonticidal drug but should not be administered until the condition of the patient stabilizes. The primaquine dose is well tolerated and prior testing for G6PD deficiency is not required.

Chemoprophylaxis

Recent studies have demonstrated that in adults a daily prophylactic dose of 30 mg of base taken during exposure and for one day after departure from a malarious area is highly efficacious in preventing P. vivax and P. falciparum infections (60, 283, 292). Although primaquine is not currently licensed for chemoprophylaxis, plans are under way to seek a change in labelling to include an indication for the prevention of P. vivax and P. falciparum infections. All persons taking this regimen should be screened for G6PD deficiency. No serious adverse events have been observed in persons using daily primaquine prophylaxis for 16-52 weeks (283).

Use in pregnancy

Primaquine is contraindicated during pregnancy because of the risk of haemolysis in the fetus, which is relatively deficient in G6PD.

Drug disposition

Primaquine is readily absorbed when taken orally but there is a considerable inter-individual variation in pharmacokinetic profile in humans. Peak plasma concentrations occur within 1-3 h, with a plasma half-life of about 5 h. Primaquine is rapidly metabolized in the liver and only a small amount is excreted unchanged in the urine, which suggests extensive intrahepatic recycling. Two major metabolic pathways have been described. One leads to the formation of 5-hydroxyprimaquine and 5-hydroxy-demethylprimaquine, both of which have antimalarial activity and cause methaemoglobin formation. The other pathway results in the formation of N-acetylprimaquine and a desamino-carboxylic acid. The carboxyclic acid metabolite is the major metabolite in humans and does not appear to be active (293).

Adverse effects

Primaquine may cause anorexia. Other adverse effects include nausea, vomiting, abdominal pain and cramps. These symptoms are dose related and are relatively rare at daily doses of up to 0.25 mg of base per kg (15 mg of base daily in an adult). Gastric intolerance can be avoided by administering the drug with food. Primaquine has also been known to cause weakness, uneasiness in the chest, anaemia, methaemoglobinaemia, leukopenia and suppression of myeloid activity.

In chemoprophylaxis trials, a daily dose of 30 mg of base in persons with normal G6PD status showed good safety and tolerance when compared with placebo and other antimalarial drugs (60, 283, 292).

The more severe adverse reactions at higher doses are related to the effect of primaquine on the formed elements of the blood and bone marrow. Primaquine does not normally cause granulocytopenia at the doses recommended for malaria therapy. The haemolytic action of primaquine is increased in subjects with G6PD deficiency. It is usually self-limiting but blood transfusions may be necessary in severe cases (110).

Contraindications

Primaquine is contraindicated in pregnancy and in children under 4 years of age because of the risk of haemolysis. The drug is also contraindicated in conditions predisposing to granulocytopenia, including active rheumatoid arthritis and lupus erythematosus.

Drug interactions

Primaquine should not be administered with any other drug that may induce haematological disorders.

Overdosage

Gastrointestinal symptoms, weakness, methaemoglobinaemia, cyanosis, haemolytic anaemia, jaundice and bone marrow depression may occur with overdosage. There is no specific antidote and treatment is symptomatic.