(1995; 152 pages) [French] [Spanish]
Group: antiprotozoal agent
Tablet 25 mg, 50 mg
An inhibitor of folic acid metabolism that acts synergistically with the sulfonamides to kill tachyzoites. The high concentrations required for the treatment of toxoplasmosis may interfere with folic acid metabolism in the patient.
The plasma half-life after oral administration is about 4 days. It is partially metabolized in the liver and ultimately excreted in the urine.
Treatment of toxoplasmosis in:
• pregnant women after the first trimester when there is a danger of congenital transmission
• infected neonates
• infants, children and adults with chorioretinitis
• patients with active toxoplasmosis who are immunodeficient as a consequence of drug treatment or disease.
Dosage and administration
In the schedules described below pyrimethamine must always be taken together with sulfadiazine.
Pyrimethamine has been administered alone to patients who are hypersensitive to sulfonamides at dosages some four times greater than those suggested here. However, such regimens are associated with a greater risk of bone-marrow depression.
The regimens proposed provide general guidance and are subject to modification in the light of ongoing studies. Recent experience, gained largely in pregnant women and patients with AIDS, suggests that better results can be obtained with doses larger than those previously recommended. This evidence has been taken into account for the recommendations made here.
Pregnant women: 25 mg daily for 3-4 weeks, but not before the second trimester. Recent experience suggests that alternating 3-week courses of pyrimethamine/sulfadiazine and of spiramycin 3 g daily until term may hold advantage.
Neonates without overt disease born to mothers infected during pregnancy: 1 mg/kg daily for 4 weeks, followed, if infection is subsequently confirmed, with further courses. Good results have been obtained by alternating 4-week courses of pyrimethamine/sulfadiazine with 6-week courses of spiramycin 100 mg/kg daily throughout the first year of life.
Neonates with overt disease: 1 mg/kg daily for 6 months. Treatment should then be continued, at least on an intermittent basis, throughout the first year of life. Good results have been obtained with alternating 4-week courses of pyrimethamine/sulfadiazine and of spiramycin 100 mg/kg daily.
Chorioretinitis in adults: 75 mg daily for 3 days, then 25 mg daily for 4 weeks. Unresponsive patients should receive 50 mg daily for a further 3-4 weeks. Further courses of pyrimethamine/sulfadiazine may be administered in the event of relapse.
Immunodeficient patients: 200 mg in divided doses for 1 day followed by 75-100 mg daily for at least 6 weeks, and then a suppressive dose of 25-50 mg daily.
• Known hypersensitivity.
• Severe hepatic or renal dysfunction.
• Pregnancy during the first trimester.
Adults and children should receive calcium folinate (3-5 mg every third day) concurrently to prevent folinic acid deficiency resulting from high daily doses of pyrimethamine.
The blood count should be monitored twice weekly throughout therapy, particularly in neonates, to detect signs of bone-marrow depression.
Concomitant administration of drugs that interfere with folic acid metabolism, other than sulfadiazine, should be avoided whenever possible.
Use in pregnancy
Pyrimethamine is contraindicated during the first trimester but should always be given thereafter when there is a danger of congenital transmission.
Anorexia, abdominal cramps, vomiting, ataxia, tremors and seizures have been reported.
At the high dosages required for the treatment of toxoplasmosis, pyrimethamine may induce thrombocytopenia, granulocytopenia and a megaloblastic anaemia due to folinic acid deficiency.
Several other drugs, including all sulfonamides, trimethoprim and methotrexate, act synergistically with pyrimethamine to inhibit folic acid metabolism. Coadministration (other than planned use of sulfadiazine) should be avoided.
Excessive doses of pyrimethamine are potentially fatal. Anorexia, vomiting and seizures are characteristic signs of overdosage. Induction of emesis or gastric lavage is of value if undertaken within a few hours of ingestion. Convulsions may be controlled with intravenous diazepam.
Tablets should be kept in well-closed containers protected from light and moisture.