pyrimethamine
Daraprim

Available forms
Available by prescription only
Tablets: 25 mg

Indications and dosages
 Malaria prophylaxis and transmission control. Adults and children older than age 10: 25 mg P.O. weekly.
Children ages 4 to 10: 12.5 mg P.O. weekly.
Children younger than age 4: 6.25 mg P.O. weekly.
 Dosage should be continued for all age-groups for at least 10 weeks after leaving endemic areas.
 Acute attacks of malaria.   Not recommended alone in nonimmune persons; use with faster-acting antimalarials, such as chloroquine, for 2 days to initiate transmission control and suppressive cure. For chloroquine-resistant strain, administer with sulfonamides and possibly quinine.
Adults and children older than age 15: 50 mg P.O. daily for 2 days followed by 25 mg once weekly for at least 10 weeks.
Children ages 4 to 10: 25 mg once daily for 2 days followed by 12.5 mg once weekly for at least 10 weeks.
 Toxoplasmosis. Adults: 50 to 75 mg P.O. daily for 3 to 4 weeks, with sulfadiazine 2 to 8 g P.O. dai Adults: 50 to 75 mg P.O. daily for 3 to 4 weeks, with sulfadiazine 2 to 8 g P.O. daily in three or four divided doses.
Children: 1 mg/kg daily P.O. (maximum daily dose is 25 mg) in divided doses q 12 hours for 3 days; then 1 mg/kg daily P.O. for 4 weeks. Administer with sulfadoxine 100 to 200 mg P.O. daily in divided doses.
 Isosporiasis ◇. Adults: 50 to 75 mg P.O. daily.

Pharmacodynamics
Antimalarial action: Inhibits the reduction of dihydrofolate to tetrahydrofolate, thereby blocking folic acid metabolism, which is needed for survival of susceptible organisms. This mechanism is distinct from sulfonamide-induced folic acid antagonism. Drug is active against the asexual erythrocytic forms of susceptible plasmodia and against Toxoplasma gondii.

Pharmacokinetics
Absorption: Well absorbed from intestinal tract.
Distribution: Distributed to kidneys, liver, spleen, and lungs; about 80% bound to plasma proteins.
Metabolism: Metabolized to several unidentified compounds.
Excretion: Excreted in urine and breast milk; elimination half-life 2 to 6 days. Half-life not changed in end-stage renal disease.

Contraindications and precautions
Contraindicated in patients hypersensitive to drug and in those with megaloblastic anemia from folic acid deficiency. Use cautiously in patients with impaired renal or hepatic function, severe allergy or bronchial asthma, G6PD deficiency, or seizure disorders and in those who have been treated with chloroquine.

Interactions
Drug-drug. Co-trimoxazole, other sulfonamides: Causes additive adverse effects. Pyrimethamine and sulfadoxine combination shouldn’t be given with these drugs.
Folic acid, para-aminobenzoic acid: Reduces antitoxoplasmic effects of pyrimethamine. May need dosage adjustment.
Lorazepam: Causes mild hepatotoxicity. Monitor liver function.
Sulfonamides: Pyrimethamine and sulfonamides act synergistically against some organisms; each inhibits folic acid synthesis at a different level. Monitor patient if used together.

Adverse reactions
GI: anorexia, vomiting, atrophic glossitis.
Hematologic: aplastic anemia, megaloblastic anemia, leukopenia, thrombocytopenia, pancytopenia.

Effects on lab test results
• May decrease hemoglobin, hematocrit and granulocyte, WBC, platelet, and RBC counts.

Overdose and treatment
Toxicity may cause anorexia, vomiting, and CNS stimulation, including seizures. Megaloblastic anemia, thrombocytopenia, leukopenia, glossitis, and crystalluria may also occur.
 Treatment of overdose consists of gastric lavage, then a cathartic; barbiturates may help to control seizures. Leucovorin (folinic acid) in a dosage of 5 to 15 mg daily P.O., I.M., or I.V. for 3 days or longer is used to restore decreased platelet or leukocyte counts.

Special considerations
• No longer considered a first-line antimalarial. Other antimalarials (mefloquine, chloroquine, sulfadoxine) are generally preferred.
• Give drug with meals to minimize GI distress.
• Monitor CBC, including platelet counts, twice weekly.
• Monitor patient for signs of folate deficiency or bleeding when platelet count is low; if abnormalities appear, decrease dosage or stop drug. Leucovorin (folinic acid) may be prescribed to raise blood counts while reducing dosage or after drug is stopped.
 ALERT Because severe reactions may occur, pyrimethamine with sulfadoxine should be given only to patient traveling to areas where chloroquine-resistant malaria is prevalent and only if traveler will be in such areas longer than 3 weeks.
Breast-feeding patients
• Pyrimethamine is contraindicated in breast-feeding women because of the risk of serious adverse reactions in breast-fed infants.
Pediatric patients
• Use cautiously in children.

Patient education
• Teach patient how to recognize signs and symptoms of adverse blood reactions and tell him to report them immediately. Teach emergency measures to control overt bleeding.
• Teach patient signs and symptoms of folate deficiency.
• Counsel patient about need to report adverse effects and to keep follow-up medical appointments.
• Tell patient to keep drug out of reach of children.

Reactions may be common, uncommon, life-threatening, or COMMON AND LIFE THREATENING.
◆ Canada only
◇ Unlabeled clinical use