Pyrimethamine warnings and precautions

# Warnings
The dosage of pyrimethamine required for the treatment of toxoplasmosis is 10 to 20 times the recommended antimalaria dosage and approaches the toxic level. If signs of folate deficiency develop (see Adverse Reactions), reduce the dosage or discontinue the drug according to the response of the patient. Folinic acid (leucovorin) should be administered in a dosage of 5 to 15 mg daily (orally, IV, or IM) until normal hematopoiesis is restored.
Data in 2 humans indicate that pyrimethamine may be carcinogenic; a 51-year-old female who developed Chronic Granulocytic Leukemia after taking pyrimethamine for 2 years for toxoplasmosis3 and a 56-year-old patient who developed reticulum cell sarcoma after 14 months of pyrimethamine for toxoplasmosis.
Pyrimethamine has been reported to produce a significant increase in the number of lung tumors in mice when given intraperitoneally at doses of 25 mg/kg.5
DARAPRIM should be kept out of the reach of infants and children as they are extremely susceptible to adverse effects from an overdose. Deaths in pediatric patients have been reported after accidental ingestion.

# Precautions

## General
The recommended dosage for chemoprophylaxis of malaria should not be exceeded. A small starting dose for toxoplasmosis is recommended in patients with convulsive disorders to avoid the potential nervous system toxicity of pyrimethamine. DARAPRIM should be used with caution in patients with impaired renal or hepatic function or in patients with possible folate deficiency, such as individuals with malabsorption syndrome, alcoholism, or pregnancy, and those receiving therapy, such as phenytoin, affecting folate levels (see Pregnancy subsection).

## Information for Patients
Patients should be warned that at the first appearance of a skin rash they should stop use of DARAPRIM and seek medical attention immediately. Patients should also be warned that the appearance of sore throat, pallor, purpura, or glossitis may be early indications of serious disorders which require treatment with DARAPRIM to be stopped and medical treatment to be sought.
Women of childbearing potential who are taking DARAPRIM should be warned against becoming pregnant. Patients should be warned to keep DARAPRIM out of the reach of children. Patients should be advised not to exceed recommended doses. Patients should be warned that if anorexia and vomiting occur, they may be minimized by taking the drug with meals.
Concurrent administration of folinic acid is strongly recommended when used for the treatment of toxoplasmosis in all patients.

## Laboratory Tests
In patients receiving high dosage, as for the treatment of toxoplasmosis, semiweekly blood counts, including platelet counts, should be performed.

## Carcinogenesis, Mutagenesis, Impairment of Fertility
See Warnings section for information on carcinogenesis.

### Mutagenesis
Pyrimethamine has been shown to be nonmutagenic in the following in vitro assays: the Ames point mutation assay, the Rec assay, and the E. coli WP2 assay. It was positive in the L5178Y/TK +/- mouse lymphoma assay in the absence of exogenous metabolic activation.6 Human blood lymphocytes cultured in vitro had structural chromosome aberrations induced by pyrimethamine. In vivo, chromosomes analyzed from the bone marrow of rats dosed with pyrimethamine showed an increased number of structural and numerical aberrations.

## Teratogenic Effects
Pregnancy Category C. Pyrimethamine has been shown to be teratogenic in rats when given in oral doses 7 times the human dose for chemoprophylaxis of malaria or 2.5 times the human dose for treatment of toxoplasmosis. At these doses in rats, there was a significant increase in abnormalities such as cleft palate, brachygnathia, oligodactyly, and microphthalmia. Pyrimethamine has also been shown to produce terata such as meningocele in hamsters and cleft palate in miniature pigs when given in oral doses 170 and 5 times the human dose, respectively, for chemoprophylaxis of malaria or for treatment of toxoplasmosis.
There are no adequate and well-controlled studies in pregnant women. DARAPRIM should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Concurrent administration of folinic acid is strongly recommended when used for the treatment of toxoplasmosis during pregnancy.

## Nursing Mothers
Pyrimethamine is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from pyrimethamine and from concurrent use of a sulfonamide with DARAPRIM for treatment of some patients with toxoplasmosis, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother (see Warnings And Precautions: Pregnancy).

## Pediatric Use
See Dosage And Administration section.

## Geriatric Use
Clinical studies of DARAPRIM did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.