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Pyrimethamine (Systemic)


VA CLASSIFICATION
Primary: AP101
Secondary: AP109

Commonly used brand name(s): Daraprim.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Antiprotozoal—

Indications

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.

Accepted

Malaria (treatment)—Pyrimethamine is indicated in combination with sulfadoxine and quinine in the treatment of chloroquine-resistant Plasmodium falciparum malaria {05} {07}. It is also indicated in combination with mefloquine and sulfadoxine, or quinine and sulfadoxine in the treatment of chloroquine-resistant P. falciparum malaria acquired in Southeast Asia, Bangladesh, East Africa, or the Amazon basin {05}. Pyrimethamine is indicated in combination with sulfadoxine in the presumptive treatment of chloroquine-resistant P. falciparum malaria for self-treatment of febrile illness when medical care is not immediately available {04} {07}.

Toxoplasmosis (treatment)—Pyrimethamine is indicated in combination with a sulfapyrimidine-type sulfonamide in the treatment of toxoplasmosis caused by Toxoplasma gondii {11}. [Pyrimethamine is also used with clindamycin in the treatment of toxoplasmosis in patients who are unresponsive to or intolerant of standard therapy]1 {13} {25} {26} {27}.

[Isosporiasis (prophylaxis and treatment)]1—Pyrimethamine is used with sulfadoxine in the prophylaxis and treatment of isosporiasis caused by Isospora belli . It has also been used alone in a limited number of patients in the prophylaxis and treatment of isosporiasis {03} {10} {11}.

[Pneumonia, Pneumocystis carinii (treatment)]1—Pyrimethamine is used in combination with sulfadiazine, sulfadoxine, or dapsone, in the treatment of mild to moderate pneumonia caused by Pneumocystis carinii in patients who are unresponsive to or intolerant of standard therapy {14}.

—Not all species or strains of a particular organism may be susceptible to pyrimethamine. Resistance to pyrimethamine has been reported in P. falciparum and Plasmodium vivax malaria and may be widespread in certain areas.

Unaccepted
Pyrimethamine is not indicated alone in the treatment of acute attacks of malaria in nonimmune patients. Fast-acting schizonticides (e.g., 4-aminoquinolines, quinine) are preferred for these patients.

1 Not included in Canadian product labeling.



Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    248.72

Mechanism of action/Effect:

Binds to and reversibly inhibits the protozoal enzyme dihydrofolate reductase, selectively blocking conversion of dihydrofolic acid to its functional form, tetrahydrofolic acid. This depletes folate, an essential cofactor in the biosynthesis of nucleic acids, resulting in interference with protozoal nucleic acid and protein production. Protozoal dihydrofolate reductase is many times more tightly bound by pyrimethamine than the corresponding mammalian enzyme {01} {02}.

Exerts its effect in the folate biosynthesis at a step immediately subsequent to the one at which sulfonamides exert their effect. When administered concurrently with sulfonamides, synergism occurs, which is attributed to inhibition of tetrahydrofolate production at two sequential steps in its biosynthesis {01} {02}.

Active against asexual erythrocytic forms and, to a lesser degree, tissue forms of P. falciparum malaria. Does not destroy gametocytes, but arrests sporogony in the mosquito. Used alone, pyrimethamine does not produce radical cure in P. vivax or Plasmodium ovale malaria since it does not kill the latent hepatic stages of these parasites {01} {02}.

Absorption:

Well absorbed following oral administration {18}.

Distribution:

Widely distributed; mainly concentrated in blood cells, kidneys, lungs, liver, and spleen {20}. Crosses into the cerebrospinal fluid (CSF), with concentrations ranging from 13 to 26% of the corresponding serum concentrations {08} {19}. The mean whole blood to plasma concentration ratio was 0.87 in one study {23}. Also crosses the placenta and is distributed into breast milk.

Vol D ranges from 2.3 to 3.1 liters per kg {18} {22} {23} {24}.

Protein binding:

High (87%) {01} {02}.

Biotransformation:

Hepatic {19}.

Half-life:

Adults—Range, 80 to 123 hours {18} {21} {22} {23} {24}. However, the half-life of pyrimethamine has been found to be as short as 23 hours in studies in patients with acquired immunodeficiency syndrome (AIDS), suggesting the possibility of a genetic variation in the metabolism of pyrimethamine or altered hepatic function secondary to HIV infection {12} {19}.

Infants (approximately 1 year old)—Approximately 64 hours (range, 52 to 87 hours) {08}.

Time to peak plasma concentration

Approximately 3 hours (range, 2 to 6 hours) {18} {21} {22} {23} {24}.

Peak plasma concentration

Adults—0.13 to 0.31 mcg/mL after a 25 mg dose {18} {23} {24}.

Infants (approximately 1 year old)—1.3 mcg/mL after a dose of 1 mg per kg of body weight (mg/kg) per day; 0.7 mcg/mL 4 hours after a dose when administered at 1 mg/kg every Monday, Wednesday, and Friday {08}.

Elimination:
    Renal—Primary route; 20 to 30% excreted unchanged in urine. Urinary excretion may persist for 30 days or longer {18}.
    In dialysis—The serum concentration of pyrimethamine fell by approximately 47% after peritoneal dialysis in one patient {19}.


Precautions to Consider

Carcinogenicity

Pyrimethamine has been reported to be associated with two cases of cancer in humans. Chronic granulocytic leukemia and reticulum cell sarcoma developed in patients receiving long-term pyrimethamine therapy for toxoplasmosis. Pyrimethamine also produced a significant increase in the number of lung tumors in mice given high-dose intraperitoneal pyrimethamine {01} {02}.

Mutagenicity

An increase in the number of structural and numerical aberrations was found in the chromosomes analyzed from the bone marrow of rats dosed with pyrimethamine. Structural chromosome aberrations were induced by pyrimethamine in human blood lymphoctyes cultured in vitro . Pyrimethamine was positive in the L5178Y/TK +/- mouse lymphoma assay without metabolic activation. However, it was found to be nonmutagenic in the Ames point mutation assay, the Rec assay, and the Escherichia coli WP2 assay {01} {02}.

Pregnancy/Reproduction
Fertility—
The fertility index of rats treated with pyrimethamine was lowered when high doses were used, suggesting possible toxic effects on the whole organism and/or conceptuses {01} {02}.

Pregnancy—
Pyrimethamine crosses the placenta. Studies in humans have not shown that pyrimethamine causes teratogenic effects. Also, use in pregnant women to date has not shown pyrimethamine to be teratogenic. However, use is not generally recommended during the first 14 to 16 weeks of pregnancy, since studies in animals have shown that pyrimethamine may cause birth defects in the fetus and may interfere with folic acid metabolism, especially when given in large doses such as those required in the treatment of toxoplasmosis. If pyrimethamine is necessary in the treatment of toxoplasmosis during pregnancy, it is recommended that leucovorin (folinic acid) be given concurrently {01} {02} {06} {15} {16} {28}.

FDA Pregnancy Category C {01}.

Breast-feeding

Pyrimethamine is distributed into breast milk. It is estimated that a nursing infant would ingest approximately 3 to 4 mg over 48 hours after the ingestion of a single 75 mg dose by the mother {01} {02}. Problems in humans have not been documented {17}. However, pyrimethamine may interfere with folic acid metabolism in nursing infants, especially when given to nursing women in large doses such as those required in the treatment of toxoplasmosis.

Pediatrics

Pyrimethamine has been used in children, and no pediatrics-specific problems have been documented to date.


Geriatrics


No information is available on the relationship of age to the effects of pyrimethamine in geriatric patients.


Dental

High doses of pyrimethamine not supplemented by leucovorin (folinic acid) may cause a folic acid deficiency, which may be characterized by a change in or loss of taste, or pain, burning, or inflammation of the tongue.

The leukopenic and thrombocytopenic effects of high doses of pyrimethamine may result in an increased incidence of certain microbial infections, delayed healing, and gingival bleeding. If leukopenia or thrombocytopenia occurs, dental work should be deferred until blood counts have returned to normal. Patients should be instructed in proper oral hygiene, including caution in use of regular toothbrushes, dental floss, and toothpicks {01} {02}.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

» Bone marrow depressants (see Appendix II )    (concurrent use of pyrimethamine with bone marrow depressants may increase the leukopenic and/or thrombocytopenic effects; if concurrent use is required, the possibility of increased myelotoxic effects should be considered, especially when pyrimethamine is used in large doses such as those required in the treatment of toxoplasmosis)


Folate antagonists, other, (see Appendix II )    (concurrent use of other folate antagonists with pyrimethamine or use of pyrimethamine between courses of other folate antagonists is not recommended because of the possible development of megaloblastic anemia {01} {02})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Risk-benefit should be considered when the following medical problems exist
» Anemia or
» Bone marrow depression    (pyrimethamine may cause folic acid deficiency, resulting in megaloblastic anemia, and blood dyscrasias, including agranulocytosis and thrombocytopenia)


Hepatic function impairment    (pyrimethamine is metabolized in the liver)


Hypersensitivity to pyrimethamine
» Seizure disorders, history of    (pyrimethamine may cause central nervous system [CNS] toxicity when used in high doses, as in the treatment of toxoplasmosis)



Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

» Complete blood counts (CBCs) and
» Platelet counts    (may be required weekly during therapy in patients receiving high dosage, as in the treatment of toxoplasmosis {01} {02})




Side/Adverse Effects

Note: When pyrimethamine is used for malaria at recommended dosages, side/adverse effects usually are rare; however, with large doses, as for treatment of toxoplasmosis, side effects may occur more frequently unless pyrimethamine is given concurrently with folinic acid.

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence less frequent
    
Agranulocytosis, leukopenia, or thrombocytopenia (black, tarry stools; blood in urine or stools; cough or hoarseness; fever or chills; lower back or side pain; painful or difficult urination; pinpoint red spots on skin; unusual bleeding or bruising){01}{02}
    
atrophic glossitis (irritation or soreness of tongue){01}{02}

Incidence rare
    
Erythema multiforme and/or Stevens-Johnson syndrome (bleeding or crusting sores on lips; chest pain; fever with or without chills; muscle cramps or pain; redness, blistering, peeling, or loosening of skin; sores, ulcers, and/or white spots in mouth; sore throat; unusual tiredness or weakness){01}{02}
    
hypersensitivity (skin rash){01}{02}



Those indicating need for medical attention only if they continue or are bothersome
Incidence less frequent
    
Anorexia (loss of appetite){01}{02}
    
diarrhea {01}{02}
    
nausea {01}{02}
    
vomiting {01}{02}





Overdose
For specific information on the agents used in the management of pyrimethamine overdose, see:
   • Barbiturates (Systemic) monograph;
   • Benzodiazepines (Systemic) monograph; and/or
   • Leucovorin (Systemic) monograph.
For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).

Clinical effects of overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Acute
In order of occurrence:
    
Gastrointestinal toxicity (abdominal pain; severe and repeated vomiting)
    
neurotoxicity (hyperexcitability; seizures)—usually occurs within 30 minutes to 2 hours of ingestion
    
respiratory depression
    
circulatory collapse
{01}{02}

Treatment of overdose
Recommended treatment for pyrimethamine overdose includes:


To decrease absorption:
Gastric emptying by aspiration and lavage {01} {02}.



Specific treatment:
Control of CNS stimulation, including seizures, by parenteral administration of benzodiazepines or short-acting barbiturates. Administration of leucovorin, 5 to 15 mg (up to 50 mg in cerebral toxoplasmosis) intramuscularly daily for 3 days or longer, to counteract the effects of folic acid antagonism (e.g., reduced white blood cell counts) induced by pyrimethamine {01} {02}.



Monitoring:
Monitoring of hematopoietic status for at least 1 month following overdose {01} {02}.

Note: Due to the long half-life of pyrimethamine, daily monitoring of peripheral blood counts is recommended up to several weeks after the overdosage until normal hematologic values are restored {01} {02}.




Supportive care:
Mechanical assistance of respiration, if necessary. Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation {01} {02}.



Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Pyrimethamine (Systemic) .

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Hypersensitivity to pyrimethamine

Pregnancy—Pyrimethamine crosses the placenta





Breast-feeding—Pyrimethamine is distributed into breast milk





Dental—High doses may cause atrophic glossitis, leukopenia, or thrombocytopenia
Other medications, especially bone marrow depressants
Other medical problems, especially anemia, bone marrow depression, or a history of seizure disorders

Proper use of this medication
» Keeping medication out of reach of children; overdose is very dangerous

Taking with meals or a snack if gastric irritation occurs

» Compliance with full course of therapy

» Importance of not missing doses and taking medication on a regular schedule

» Proper dosing
Missed dose: Taking as soon as possible; not taking if almost time for next dose; not doubling doses

» Proper storage

Precautions while using this medication
» Regular visits to physician to check blood counts, especially during high-dose therapy for toxoplasmosis

Checking with physician if no improvement within a few days

Importance of taking leucovorin concurrently if anemia occurs

Using caution in use of regular toothbrushes, dental floss, and toothpicks; deferring dental work until blood counts have returned to normal; checking with physician or dentist concerning proper oral hygiene


Side/adverse effects
Signs of potential side effects, especially agranulocytsis, leukopenia, or thrombocytopenia; atrophic glossitis; erythema multiforme and/or Stevens-Johnson syndrome; and hypersensitivity


General Dosing Information
Pyrimethamine may cause gastric irritation, sometimes resulting in vomiting, when given in high doses {01} {02}. To minimize this, pyrimethamine may be taken with meals or a snack or the dosage may be reduced {01} {02}.

Therapy should be discontinued if symptoms of folic acid deficiency occur. However, to prevent folic acid deficiency, leucovorin (folinic acid) may be administered concurrently to restore normal hematopoiesis. Leucovorin does not interfere with the antiprotozoal activity of pyrimethamine. Since malarial parasites are unable to utilize preformed folic acid, the antimalarial effect of pyrimethamine should not be affected {09}. However, folic acid may interfere with the action of pyrimethamine on Toxoplasma gondii , and concurrent use in toxoplasmosis is not recommended {14}. In adults, 5 to 15 mg of leucovorin may be given orally, intramuscularly, or intravenously once a day for 3 days or as required. Alternatively, adults may be given 9 mg of leucovorin two or three times a week. Doses of up to 50 mg per day of leucovorin have been used with pyrimethamine in AIDS patients {27}. Infants may be given 1 mg of leucovorin once a day {01} {02}.

Patients with impaired renal function receiving pyrimethamine prophylactically do not generally require a reduction in dose. However, patients receiving pyrimethamine more frequently should be monitored closely for signs of toxicity.
For toxoplasmosis
The dose of pyrimethamine that is required in the treatment of toxoplasmosis is 10 to 20 times greater than the antimalarial dose. Concurrent prophylactic administration of leucovorin in doses of up to 50 mg daily with pyrimethamine is recommended to avoid folic acid deficiency.

In patients with seizure disorders, small initial doses of pyrimethamine are recommended in the treatment of toxoplasmosis to avoid potential CNS toxicity.

In patients who also have AIDS, treatment with pyrimethamine and sulfonamides may be required indefinitely. Clindamycin has been used with pyrimethamine in doses of 900 mg to 2.4 grams daily in patients who experienced adverse reactions to sulfonamides {13} {25} {26}.



Oral Dosage Forms

Note: Bracketed uses in the Dosage Forms section refer to categories of use and/or indications that are not included in U.S. product labeling.

PYRIMETHAMINE TABLETS USP

Usual adult and adolescent dose
Malaria


Treatment:
Chloroquine-resistant Plasmodium falciparum malaria—Oral, 75 mg of pyrimethamine in combination with 1.5 grams of sulfadoxine as a single dose on day three of quinine therapy.

Chloroquine-resistant P. falciparum malaria acquired in Southeast Asia, Bangladesh, East Africa, or the Amazon basin—Oral, 75 mg of pyrimethamine in combination with 750 mg of mefloquine and 1.5 grams of sulfadoxine as a single dose {05}.



Presumptive treatment:
Oral, 75 mg of pyrimethamine in combination with 1.5 grams of sulfadoxine as a single dose for self-treatment of febrile illness when medical care is not immediately available {06} {07}.


Toxoplasmosis


AIDS patients {27}:
Loading dose—Oral, 100 to 200 mg of pyrimethamine per day in combination with 500 mg to 1.5 grams of a sulfadiazine every six hours, or 600 mg of clindamycin every six hours, for one to two days.

Treatment—Oral, 50 to 100 mg of pyrimethamine per day in combination with 500 mg to 1.5 grams of a sulfadiazine every six hours, or 600 mg of clindamycin every six hours, for three to six weeks.

Maintenance—Oral, 25 to 50 mg of pyrimethamine per day in combination with 250 mg to 1 gram of a sulfadiazine every six hours, or 600 mg of clindamycin every six hours, as life-long therapy.



Other patients {01} {02}:
Loading dose—Oral, 50 to 200 mg per day in combination with 250 mg to 1 gram of a sulfapyrimidine-type sulfonamide every six hours, for one to two days.

Treatment—Oral, 25 to 50 mg per day in combination with 125 to 500 mg of a sulfapyrimidine-type sulfonamide every six hours, for two to four weeks if patient is immunocompetent, and four to six weeks if patient is immunocompromised.


[Isosporiasis]1{03} {10} {11}
Treatment: Oral, 50 to 75 mg of pyrimethamine per day for three to four weeks.

Prophylaxis: Oral, 25 mg of pyrimethamine in combination with 500 mg of sulfadoxine once a week; or 25 mg of pyrimethamine alone once a day.

Note: These doses are based on very limited data.



Usual pediatric dose
Malaria


Treatment:
Chloroquine-resistant P. falciparum malaria—Oral, 1.25 mg per kg of body weight of pyrimethamine in combination with 25 mg per kg of body weight of sulfadoxine as a single dose on day three of quinine therapy.

Chloroquine-resistant P. falciparum malaria acquired in Southeast Asia, Bangladesh, East Africa, or the Amazon basin—Oral, 1 mg per kg of body weight of pyrimethamine in combination with 10 mg per kg of body weight of mefloquine and 20 mg per kg of body weight of sulfadoxine as a single dose {05}.



Presumptive treatment, for self-treatment of febrile illness when medical care is not immediately available {06} {07}:
Children 5 to 10 kg of body weight—Oral, 12.5 mg of pyrimethamine and 250 mg of sulfadoxine combination (1/2 tablet) as a single dose.

Children 11 to 20 kg of body weight—Oral, 25 mg of pyrimethamine and 500 mg of sulfadoxine combination (1 tablet) as a single dose.

Children 21 to 30 kg of body weight—Oral, 37.5 mg of pyrimethamine and 750 mg of sulfadoxine combination (11/2 tablets) as a single dose.

Children 31 to 45 kg of body weight—Oral, 50 mg of pyrimethamine and 1 gram of sulfadoxine combination (2 tablets) as a single dose.

Children greater than 45 kg of body weight—Oral, 75 mg of pyrimethamine and 1.5 grams of sulfadoxine combination (3 tablets) as a single dose.


Toxoplasmosis
In combination with the usual pediatric dose of a sulfapyrimidine-type sulfonamide: Oral, 1 mg of pyrimethamine per kg of body weight once a day for one to three days; then 0.5 mg of pyrimethamine per kg of body weight once a day for four to six weeks.

Note: In infants with confirmed congenital toxoplasmosis, treatment should be continued for a minimum of six months if there are no signs of infection, and for one year if there are signs of significant infection.



Strength(s) usually available
U.S.—


25 mg (Rx) [Daraprim (scored){01}]

Canada—


25 mg (Rx) [Daraprim (scored){02}]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a tight, light-resistant container {01} {02}.

Preparation of dosage form:
For patients who cannot take oral solids—According to the manufacturer, the tablets may be crushed to prepare a 1% solution in normal saline. The solution is stable for 24 hours at room temperature. Cherry Syrup NF or sucrose-containing solutions may also be used as vehicles. However, pyrimethamine prepared in these vehicles should be used immediately after preparation.

Auxiliary labeling:
   • Continue medicine for full time of treatment.
   • Keep out of reach of children.

Note: Explain potential danger of accidental overdose.
Consider dispensing in unit-dose packaging in child-resistant containers (“double-barrier” packaging) {01} {02}.




Revised: 05/18/1999



References
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  1. Mansor SM. Single dose kinetic study of the triple combination mefloquine/sulphadoxine/pyrimethamine (Fansimef) in healthy male volunteers. Br J Clin Pharmacol 1989; 27(3): 381-6.
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  1. Leport C. An open study of the pyrimethamine-clindamycin combination in AIDS patients with brain toxoplasmosis. J Infect Dis 1989; 160(3): 557-8.
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