PYRIMETHAMINE
DESCRIPTION:
DARAPRIM (pyrimethamine) is an antiparasitic compound available in tablet form
for oral administration. Each scored tablet contains 25 mg pyrimethamine and the
inactive ingredients corn and potato starch, lactose, and magnesium stearate.
Pyrimethamine is known chemically as 5-(4-chlorophenyl)-6-ethyl-2,4-
pyrimidinediamine.
ACTIONS/CLINICAL PHARMACOLOGY:
Pyrimethamine is well absorbed with peak levels occurring between 2 to 6 hours
following administration. It is eliminated slowly and has a plasma half-life of
approximately 96 hours. Pyrimethamine is 87% bound to human plasma proteins.
MICROBIOLOGY: Pyrimethamine is a folic acid antagonist and the rationale for its
therapeutic action is based on the differential requirement between host and
parasite for nucleic acid precursors involved in growth. This activity is highly
selective against plasmodia and Toxoplasma Gondii.
Pyrimethamine possesses blood schizonticidal and some tissue schizonticidal
activity against malaria parasites of humans. However, the 4-amino-quinoline
compounds are more effective against the erythrocytic schizonts. It does not
destroy gametocytes, but arrests sporogony in the mosquito.
pyrimethamine against Toxoplasma Gondii is greatly enhanced when used in
conjunction with sulfonamides. This was demonstrated by Eyles and Coleman
(REF.1) in the treatment of experimental toxoplasmosis in the mouse. Jacobs et
al (REF. 2) demonstrated that combination of the two drugs effectively prevented
the development of severe uveitis in most rabbits following the inoculation of
the anterior chamber of the eye with toxoplasma.
INDICATIONS AND USAGE:
TREATMENT OF TOXOPLAMOSIS: DARAPRIM is indicated for the treatment of
toxoplasmosis when used conjointly with a sulfonamide, since synergism exists
with this combination.
TREATMENT OF ACUTE MALARIA: DARAPRIM is also indicated for the treatment of
acute malaria. It should not be used alone to treat acute malaria. Fast-acting
schizonticides such as chloroquine or quinine are indicated and preferable for
the treatment of acute malaria. However, conjoint use of DARAPRIM with a
sulfonamide (e.g., sulfadoxine) will initiate transmission control and
suppression of susceptible strains of plasmodia.
CHEMOPROPHYLAXIS OF MALARIA: DARAPRIM is indicated for the chemoprophylaxis of
malaria due to susceptible strains of plasmodia. However, resistance to
pyrimethamine is prevalent worldwide. It is not suitable as a prophylactic agent
for travelers to most areas.
CONTRAINDICATIONS:
Use of DARAPRIM is contraindicated in patients with known hypersensitivity to
pyrimethamine. Use of the drug is also contraindicated in patients with
documented megaloblastic anemia due to folate deficiency.
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 two humans indicate that pyrimethamine may be carcinogenic: a 51-year-
old female who developed chronic granulocytic leukemia after taking
pyrimethamine for 2 years for toxoplasmosis, (REF. 3) and a 56 -year-old patient
who developed reticulum cell sarcoma after 14 months of pyrimethamine for
toxoplasmosis. (REF. 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. (REF.
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, such as sulfonamides or trimethoprim-sulfamethoxazole
combinations, 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. (REF. 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, 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.
DRUG INTERACTIONS:
Pyrimethamine may be used with sulfonamides, quinine and other antimalarials,
and with other antibiotics. However, the concomitant use of other antifolic
drugs, such as sulfonamides or trimethoprim-sulfamethoxazole combinations, 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.
(See Also PRECAUTIONS.)
ADVERSE REACTIONS:
Hypersensitivity reactions, occasionally severe (such as Stevens-Johnson
syndrome, toxic epidermal necrolysis, erythema multiforme, and anaphylaxis), and
hyperphenylalaninemia, can occur particularly when pyrimethamine is administered
concomitantly with a sulfonamide. With doses of pyrimethamine used for the
treatment of toxoplasmosis, anorexia and vomiting may occur. Vomiting may be
minimized by giving the medication with meals; it usually disappears promptly
upon reduction of dosage. Doses used in toxoplasmosis may produce megaloblastic
anemia, leukopenia, thrombocytopenia, pancytopenia, atrophic glossitis,
hematuria, and disorders of cardiac rhythm. Hematologic effects, however, may
also occur at low doses in certain individuals (see PRECAUTIONS: General).
Pulmonary eosinophilia has been reported rarely.
OVERDOSAGE:
Following the ingestion of 300 mg or more of pyrimethamine, gastrointestinal
and/or central nervous system signs may be present, including convulsions. The
initial symptoms are usually gastrointestinal and may include abdominal pain,
nausea, severe and repeated vomiting, possibly including hematemesis. Central
nervous system toxicity may be manifest by initial excitability, generalized and
prolonged convulsions which may be followed by respiratory depression,
circulatory collapse, and death within a few hours. Neurological symptoms appear
rapidly (30 minutes to 2 hours after drug ingestion), suggesting that in gross
overdosage pyrimethamine has a direct toxic effect on the central nervous
system.
The fatal dose is variable, with the smallest reported fatal single dose being
375 mg. There are, however, reports of pediatric patients who have recovered
after taking 375 to 625 mg.
There is no specific antidote to acute pyrimethamine poisoning. In the event of
overdosage, symptomatic and supportive measures should be employed. Gastric
lavage is recommended and is effective if carried out very soon after drug
ingestion. Parenteral diazepam may be used to control convulsions. Folinic acid
should also be administered within 2 hours of drug ingestion to be most
effective in counteracting the effects on the hematopoietic system (see
WARNINGS). Due to the long half-life of pyrimethamine, daily monitoring of
peripheral blood counts is recommended for up to several weeks after the
overdose until normal hematologic values are restored.
DOSAGE AND ADMINISTRATION:
FOR TREATMENT OF TOXOPLASMOSIS: The dosage of DARAPRIM for the treatment of
toxoplasmosis must be carefully adjusted so as to provide maximum therapeutic
effect and a minimum of side effects. At the dosage required, there is a marked
variation in the tolerance to the drug. Young patients may tolerate higher doses
than older individuals. Concurrent administration of folinic acid is strongly
recommended in all patients.
The adult Starting dose is 50 to 75 mg of the drug daily, together with 1 to 4 g
daily of a sulfonamide of the sulfapyrimidine type, e.g., sulfadoxine. This
dosage is ordinarily continued for 1 to 3 weeks, depending on the response of
the patient and tolerance to therapy. The dosage may then be reduced to about
one-half that previously given for each drug and continued for an additional 4
to 5 weeks. The pediatric dosage of DARAPRIM is 1 mg/kg per day divided into two
equal daily doses; after 2 to 4 days this dose may be reduced to one-half and
continued for approximately 1 month. The usual pediatric sulfonamide dosage is
used in conjunction with DARAPRIM.
FOR TREATMENT OF ACUTE MALARIA: DARAPRIM is NOT recommended alone in the
treatment of acute malaria. Fast- acting schizonticides, such as chloroquine or
quinine, are indicated for treatment of acute malaria. However, DARAPRIM at a
dosage of 25 mg daily for 2 days with a sulfonamide will initiate transmission
control and suppression of non-falciparum malaria. DARAPRIM is only recommended
for patients infected in areas where susceptible plasmodia exist. Should
circumstances arise wherein DARAPRIM must be used alone in semi-immune persons,
the adult dosage for acute malaria is 50mg for 2 days; children 4 through 10
years old may be given 25 mg daily for 2 days. In any event, clinical cure
should be followed by the once-weekly regimen described below for
chemoprophylaxis. Regimens which include suppression should be extended through
any characteristic periods of early recrudescence and late relapse, i.e., for at
least 10 weeks in each case.
FOR CHEMOPROPHYLAXIS OF MALARIA:
Adults and pediatric patients over 10 years- -25 mg (1 tablet) once weekly
Children 4 through 10 years--12.5 mg ( 1/2 tablet) once weekly
Infants and children under 4 years--6.25 mg ( 1/4 tablet) once weekly
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