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.4
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.
Drug Interactions: Pyrimethamine may be used with sulfonamides, quinine and
other antimalarials, and with other antibiotics. However, the
concomitant use of other antifolic drugs or agents associated
with myelosuppression including sulfonamides or
trimethoprim-sulfamethoxazole combinations, proguanil,
zidovudine, or cytostatic agents (e.g., methotrexate), while the
patient is receiving pyrimethamine, may increase the risk of
bone marrow suppression. If signs of folate deficiency develop,
pyrimethamine should be discontinued. Folinic acid (leucovorin)
should be administered until normal hematopoiesis is restored
(see WARNINGS). Mild hepatotoxicity has been reported in some
patients when lorazepam and pyrimethamine were administered
concomitantly.
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.
Pregnancy:
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.
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