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  • CLASSES

    Agents for Toxoplasmosis

    DEA CLASS

    Rx

    DESCRIPTION

    Synthetic antiparasitic agent with slow schizonticidal activity
    Used for the treatment of toxoplasmosis in combination with sulfadoxine
    Only available through the DARAPRIM Direct Program

    COMMON BRAND NAMES

    Daraprim

    HOW SUPPLIED

    Daraprim Oral Tab: 25mg

    DOSAGE & INDICATIONS

    For the treatment of toxoplasmosis, including toxoplasmic encephalitis.
    For acquired toxoplasmosis in combination with sulfadiazine.
    Oral dosage
    Adults

    50 to 75 mg PO once daily, in combination with 1 to 4 g/day of sulfadiazine, for 1 to 3 weeks, followed by one-half dose of each drug for an additional 4 to 5 weeks.

    Pregnant females

    50 mg PO twice daily for 2 days, followed by 50 mg PO once daily in combination with sulfadiazine and leucovorin is recommended by American Academy of Pediatrics (AAP) guidelines. Treatment is recommended for women who are pregnant 18 weeks or more with suspected or confirmed acute infection acquired at or after 18 weeks of pregnancy, a positive AF PCR test, or an abnormal fetal ultrasound suggestive of congenital toxoplasmosis. Pyrimethamine should not be used before 18 weeks of pregnancy due to potentially teratogenic effects. The FDA-approved dosage is 50 to 75 mg PO once daily in combination with sulfadiazine for 1 to 3 weeks, followed by one-half dose of each drug for an additional 4 to 5 weeks.

    Infants, Children, and Adolescents

    2 mg/kg/dose PO once daily (Max: 50 mg/day) for 2 days, followed by 1 mg/kg/dose PO once daily (Max: 25 mg/day) in combination with sulfadiazine, clindamycin, atovaquone, or sulfamethoxazole; trimethoprim for 3 to 6 weeks is recommended by the American Academy of Pediatrics (AAP). The FDA-approved dosage is 1 mg/kg/day PO divided every 12 hours for 2 to 4 days, followed by 0.5 mg/kg/day PO for approximately 1 month in combination with sulfadiazine.

    For the treatment of congenital toxoplasmosis.
    Oral dosage
    Infants and Children

    2 mg/kg/day PO divided twice daily (Max: 50 mg/day) for 2 days, followed by 1 mg/kg/dose PO once daily (Max: 25 mg/day) in combination with leucovorin plus sulfadiazine is recommended for infants/older children diagnosed beyond the neonatal period with active disease (chorioretinitis) by the American Academy of Pediatrics (AAP) guidelines. Continue treatment for at least 1 to 2 weeks after resolution of signs and symptoms and for 4 to 6 weeks total.

    Neonates

    2 mg/kg/day PO divided twice daily for 2 days, followed by 1 mg/kg/day PO for 2 to 6 months, then 1 mg/kg/dose PO 3 times weekly in combination with sulfadiazine and leucovorin for a total of 12 months is recommended by the American Academy of Pediatrics (AAP) guidelines.

    For the treatment of toxoplasmosis or toxoplasmic encephalitis in HIV-infected patients.
    Oral dosage
    Adults weighing 60 kg or more

    200 mg PO as a single dose, followed by 75 mg PO once daily in combination with sulfadiazine plus leucovorin is recommended by the HIV guidelines. Alternatively, pyrimethamine and leucovorin can be combined with clindamycin, atovaquone, or azithromycin. Treatment duration should be at least 6 weeks; however, a longer duration may be necessary if clinical or radiologic disease is extensive or if the response is incomplete at 6 weeks. Adjunctive corticosteroids may be administered when clinically indicated for the treatment of mass effect attributed to focal lesions or associated edema; however, discontinue as soon as possible. Anticonvulsants may be administered to patients with a seizure history during the acute treatment phase; however, they should not be used prophylactically. Chronic maintenance therapy should begin after acute treatment.

    Adults weighing less than 60 kg

    200 mg PO as a single dose, followed by 50 mg PO once daily in combination with sulfadiazine plus leucovorin is recommended by the HIV guidelines. Alternatively, pyrimethamine and leucovorin can be combined with clindamycin, atovaquone, or azithromycin. Treatment duration should be at least 6 weeks; however, a longer duration may be necessary if clinical or radiologic disease is extensive or if the response is incomplete at 6 weeks. Adjunctive corticosteroids may be administered when clinically indicated for the treatment of mass effect attributed to focal lesions or associated edema; however, discontinue as soon as possible. Anticonvulsants may be administered to patients with a seizure history during the acute treatment phase; however, they should not be used prophylactically. Chronic maintenance therapy should begin after acute treatment.

    Adolescents weighing 60 kg or more

    200 mg PO as a single dose, followed by 75 mg PO once daily in combination with sulfadiazine plus leucovorin is recommended by the HIV guidelines. Alternatively, pyrimethamine and leucovorin can be combined with clindamycin, atovaquone, or azithromycin. Treatment duration should be at least 6 weeks; however, a longer duration may be necessary if clinical or radiologic disease is extensive or if the response is incomplete at 6 weeks. Adjunctive corticosteroids may be administered when clinically indicated for the treatment of mass effect attributed to focal lesions or associated edema; however, discontinue as soon as possible. Anticonvulsants may be administered to patients with a seizure history during the acute treatment phase; however, they should not be used prophylactically. Chronic maintenance therapy should begin after acute treatment.

    Adolescents weighing less than 60 kg

    200 mg PO as a single dose, followed by 50 mg PO once daily in combination with sulfadiazine plus leucovorin recommended by the HIV guidelines. Alternatively, pyrimethamine and leucovorin can be combined with clindamycin, atovaquone, or azithromycin. Treatment duration should be at least 6 weeks; however, a longer duration may be necessary if clinical or radiologic disease is extensive or if the response is incomplete at 6 weeks. Adjunctive corticosteroids may be administered when clinically indicated for the treatment of mass effect attributed to focal lesions or associated edema; however, discontinue as soon as possible. Anticonvulsants may be administered to patients with a seizure history during the acute treatment phase; however, they should not be used prophylactically. Chronic maintenance therapy should begin after acute treatment.

    Infants and Children

    2 mg/kg/dose PO once daily (Max: 50 mg/day) for the first 3 days, followed by 1 mg/kg/dose PO once daily (Max: 25 mg/day) in combination with sulfadiazine plus leucovorin is recommended by the HIV guidelines. Treat for at least 6 weeks (depending on clinical and radiologic response), then chronic suppressive therapy (secondary prophylaxis). For sulfonamide-intolerant patients, clindamycin may be substituted for sulfadiazine.

    For toxoplasmosis prophylaxis† in immunocompromised patients.
    For primary toxoplasmosis prophylaxis† in HIV-infected patients.
    Oral dosage
    Adults

    As alternative therapy, the HIV guidelines recommend 50 mg PO once weekly with weekly leucovorin and daily dapsone OR 75 mg PO once weekly with weekly leucovorin and dapsone. Another alternative regimen of pyrimethamine 25 mg PO once daily with daily leucovorin and atovaquone may be used. Primary prophylaxis is recommended in Toxoplasma-seropositive patients with CD4 count less than 100 cells/mm3 who cannot tolerate co-trimoxazole. Primary prophylaxis for TE may be discontinued in patients who have responded to highly active antiretroviral therapy with an increase in CD4 counts to more than 200 cells/mm3 for at least 3 months. Prophylaxis should be restarted if the CD4 count decreases to less than 100 to 200 cells/mm3.

    Adolescents

    As alternative therapy, the HIV guidelines recommend 50 mg PO once weekly with weekly leucovorin and daily dapsone OR 75 mg PO once weekly with weekly leucovorin and dapsone. Another alternative regimen of pyrimethamine 25 mg PO once daily with daily leucovorin and atovaquone may be used. Primary prophylaxis is recommended in Toxoplasma-seropositive patients with CD4 count less than 100 cells/mm3 who cannot tolerate co-trimoxazole. Primary prophylaxis for TE may be discontinued in patients who have responded to highly active antiretroviral therapy with an increase in CD4 counts to more than 200 cells/mm3 for at least 3 months. Prophylaxis should be restarted if the CD4 count decreases to less than 100 to 200 cells/mm3.

    Infants and Children

    As alternative therapy, the HIV guidelines recommend 1 mg/kg/dose PO once daily (Max: 25 mg/day) in combination with either leucovorin plus dapsone or in combination with leucovorin plus atovaquone (children 4 to 24 months only) in Toxoplasma-seropositive patients with severe immunosuppression (i.e., infants and children younger than 6 years with a CD4 percentage less than 15%; or children 6 years and older with a CD4 count less than 100 cells/mm3). HIV-infected infants and infants whose infection status remains unknown should continue to receive prophylaxis for the first year of life. For children 1 to 5 years of age, primary prophylaxis may be discontinued after at least 6 months of antiretroviral therapy and with a CD4 percentage at least 15% for more than 3 consecutive months. For children 6 years and older, primary prophylaxis may be discontinued after at least 6 months of antiretroviral therapy and with a CD4 count greater than 200 cells/mm3 for more than 3 consecutive months.

    For secondary toxoplasmosis prophylaxis† in HIV-infected patients who have been treated for an acute episode of toxoplasmosis encephalitis.
    Oral dosage
    Adults

    The HIV guidelines recommend a regimen of 25 to 50 mg PO once daily with leucovorin plus sulfadiazine. Alternative regimens include pyrimethamine 25 to 50 mg PO once daily with leucovorin plus clindamycin (additional PCP prophylaxis needed) or pyrimethamine 25 mg PO once daily plus leucovorin with atovaquone. Secondary prophylaxis may be discontinued in asymptomatic patients who have a sustained increase in their CD4 counts to more than 200 cells/mm3 following highly active antiretroviral therapy for at least 6 months; however, limited numbers of patients have been evaluated and recurrences have been observed. Secondary prophylaxis should be reintroduced if the CD4 count decreases to less than 200 cells/mm3.

    Adolescents

    The HIV guidelines recommend a regimen of 25 to 50 mg PO once daily with leucovorin plus sulfadiazine. Alternative regimens include pyrimethamine 25 to 50 mg PO once daily with leucovorin plus clindamycin (additional PCP prophylaxis needed) or pyrimethamine 25 mg PO once daily plus leucovorin with atovaquone. Secondary prophylaxis may be discontinued in asymptomatic patients who have a sustained increase in their CD4 counts to more than 200 cells/mm3 following highly active antiretroviral therapy for at least 6 months; however, limited numbers of patients have been evaluated and recurrences have been observed. Secondary prophylaxis should be reintroduced if the CD4 count decreases to less than 200 cells/mm3.

    Infants and Children

    The HIV guidelines recommend 1 mg/kg/dose or 15 mg/m2/dose PO once daily (Max: 25 mg/day) in combination with leucovorin and sulfadiazine as the preferred secondary prophylaxis regimen. Alternatively, the pyrimethamine and leucovorin combination can be administered with clindamycin (additional PCP prophylaxis needed); a combination of atovaquone, leucovorin, trimethoprim/sulfamethoxazole with or without pyrimethamine is another alternative regimen. For children 1 to 5 years of age, secondary prophylaxis may be discontinued after at least 6 months of antiretroviral therapy and with a CD4 percentage of at least 15% for more than 6 consecutive months. For children at least 6 years of age, secondary prophylaxis may be discontinued after at least 6 months of antiretroviral therapy and with a CD4 count greater than 200 cells/mm3 for more than 6 consecutive months. Additionally, in order to safely discontinue secondary prophylaxis, children must also have completed initial therapy for toxoplasmic encephalitis and be asymptomatic.

    For primary Pneumocystis pneumonia (PCP) prophylaxis† in HIV-infected patients or as secondary prophylaxis in HIV-infected patients who have been treated for an acute episode of Pneumocystis pneumonia.
    Oral dosage
    Adults

    As an alternative regimen, the HIV guidelines recommend pyrimethamine 50 mg PO plus leucovorin (25 mg PO) once weekly in combination with dapsone (50 mg PO daily) or pyrimethamine 75 mg PO plus leucovorin (25 mg PO) in combination with dapsone (200 mg PO) once weekly for both primary and secondary prophylaxis. These regimens also provide effective prophylaxis against Toxoplasma gondii. The guidelines also suggest as alternative therapy, a regimen of pyrimethamine 25 mg PO plus leucovorin (10 mg PO) in combination with atovaquone (1,500 mg PO) daily for both primary and secondary prophylaxis. Primary prophylaxis is recommended in patients with CD4 count less than 200 cells/mm3, CD4 percentage less than 14% or a history of AIDS-defining illness such as oropharyngeal candidiasis, or CD4 count greater than 200 but less than 250 cells/mm3 if CD4 count monitoring every 3 months is not possible. Primary or secondary PCP prophylaxis may be discontinued when the CD4 count is greater than or equal to 200 cells/mm3 for more than 3 months in response to highly active antiretroviral therapy. Primary or secondary prophylaxis should be restarted if the CD4 count falls to less than 200 cells/mm3. If PCP is diagnosed or recurs with a CD4 count greater than 200 cells/mm3, prophylaxis is lifelong.

    Adolescents

    As an alternative regimen, the HIV guidelines recommend pyrimethamine 50 mg PO plus leucovorin (25 mg PO) once weekly in combination with dapsone (50 mg PO daily) or pyrimethamine 75 mg PO plus leucovorin (25 mg PO) in combination with dapsone (200 mg PO) once weekly for both primary and secondary prophylaxis. These regimens also provide effective prophylaxis against Toxoplasma gondii. The guidelines also suggest as alternative therapy, a regimen of pyrimethamine 25 mg PO plus leucovorin (10 mg PO) in combination with atovaquone (1,500 mg PO) daily for both primary and secondary prophylaxis. Primary prophylaxis is recommended in patients with CD4 count less than 200 cells/mm3, CD4 percentage less than 14% or a history of AIDS-defining illness such as oropharyngeal candidiasis, or CD4 count greater than 200 but less than 250 cells/mm3 if CD4 count monitoring every 3 months is not possible. Primary or secondary PCP prophylaxis may be discontinued when the CD4 count is greater than or equal to 200 cells/mm3 for more than 3 months in response to highly active antiretroviral therapy. Primary or secondary prophylaxis should be restarted if the CD4 count falls to less than 200 cells/mm3. If PCP is diagnosed or recurs with a CD4 count greater than 200 cells/mm3, prophylaxis is lifelong.

    For the treatment of isosporiasis† in immunocompromised patients.
    For chronic maintenance therapy† (secondary prophylaxis) in HIV-infected patients.
    Oral dosage
    Adults

    25 mg PO once daily plus leucovorin is recommended by the HIV guidelines as an alternative. Secondary prophylaxis should continue until CD4 count is at least 200 cells/mm3 for at least 6 months after antiretroviral therapy has been initiated and there is no further evidence of I. belli infection.

    Adolescents

    25 mg PO once daily plus leucovorin is recommended by the HIV guidelines as an alternative. Secondary prophylaxis should continue until CD4 count is at least 200 cells/mm3 for at least 6 months after antiretroviral therapy has been initiated and there is no further evidence of I. belli infection.

    Oral dosage
    Adults

    50 to 75 mg PO once daily plus leucovorin for 10 days is recommended as an alternative for sulfa-intolerant patients by the HIV guidelines.

    Adolescents

    50 to 75 mg PO once daily plus leucovorin for 10 days is recommended as an alternative for sulfa-intolerant patients by the HIV guidelines.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    75 mg/day PO.

    Geriatric

    75 mg/day PO.

    Adolescents

    75 mg/day PO.

    Children

    1 mg/kg/day is FDA-approved maximum dosage; however, doses up to 2 mg/kg/day (Max: 50 mg/day) are used off-label.

    Infants

    1 mg/kg/day is FDA-approved maximum dosage; however, doses up to 2 mg/kg/day are used off-label.

    Neonates

    1 mg/kg/day is FDA-approved maximum dosage; however, doses up to 2 mg/kg/day are used off-label.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Use cautiously in patients with hepatic impairment. Specific dosage recommendations are not available.

    Renal Impairment

    No dosage adjustment needed.

    ADMINISTRATION

     
    NOTE: Pyrimethamine is only available through a special pharmacy program, DARAPRIM Direct Program. For information on prescribing and patient enrollment, telephone 800—222—4991.

    Oral Administration

    Pyrimethamine is administered orally.

    Extemporaneous Compounding-Oral

    An extemporaneous suspension may be prepared by crushing one 25 mg tablet and adding it to 25 ml of distilled water, cherry syrup or sucrose-containing solution to make a concentration of 1 mg/ml of pyrimethamine. Shake well prior to administration. If cherry syrup or sucrose-containing solutions are used the suspension is stable for 5—7 days when stored at room temperature.

    STORAGE

    Daraprim:
    - Protect from light
    - Store between 59 to 77 degrees F
    - Store in a dry place

    CONTRAINDICATIONS / PRECAUTIONS

    Bone marrow suppression, folate deficiency, folate deficiency megaloblastic anemia

    Pyrimethamine is contraindicated in patients with folate deficiency megaloblastic anemia. Use of pyrimethamine should be avoided in patients with any preexisting anemia because folic acid antagonism can potentiate the disease. Any patient with folate deficiency should be treated with extreme caution, particularly during the treatment of toxoplasmosis, for which higher doses are used. If folate deficiency megaloblastic anemia occurs, pyrimethamine therapy should be discontinued. If therapy cannot be discontinued, a lower dosage should be considered and/or folinic acid should be administered. CBCs should be monitored regularly, especially when pyrimethamine doses greater than 25 mg/day are prescribed. Some clinicians routinely prescribe folinic acid when administering high doses of pyrimethamine. Pyrimethamine should be used with caution in patients with bone marrow suppression because myelosuppression can lead to leukopenia, agranulocytosis, or thrombocytopenia.

    Intramuscular injections

    Intramuscular injections should be used with caution in patients receiving pyrimethamine. IM injections may cause bleeding, bruising, or hematomas due to thrombocytopenia secondary to pyrimethamine-induced bone marrow suppression.

    Dental disease, dental work

    Pyrimethamine should be used with caution in patients with dental disease. Pyrimethamine can cause myelosuppression and there may be an increased risk of infection. Dental work should be performed prior to initiating pyrimethamine therapy or deferred until blood counts return to normal. Patients should be instructed on proper oral hygiene.

    Alcoholism

    Pyrimethamine should be used with caution in patients with history of alcoholism because of possible malabsorption.

    Seizure disorder

    Pyrimethamine should be used with caution in patients with a seizure disorder, especially when given for the treatment of toxoplasmosis, because high doses of the drug can precipitate a seizure.

    Hepatic disease

    Pyrimethamine, either alone or in combination with a sulfonamide, should be used with caution in patients with hepatic disease because pyrimethamine is metabolized in the liver.

    Renal disease

    Pyrimethamine, either alone or in combination with a sulfonamide, should be used with caution in renal disease. Because of the potential for sulfonamides to induce crystalluria, adequate intake of fluid must be maintained. Serum creatinine should be assessed prior to prescribing pyrimethamine.

    Asthma

    Allergic reactions can occur during therapy with pyrimethamine. The drug should be discontinued at the first sign of rash or if any change in blood cells is noted. Pyrimethamine in combination with a sulfonamide should be used with caution in patients with bronchial asthma because they are at risk of developing allergic reactions.

    Pregnancy

    Pyrimethamine is classified as pregnancy category C. Pyrimethamine alone, or in combination with a sulfonamide, should be used with extreme caution during pregnancy. Use in the first 14—16 weeks is not recommended because of possible interference in folic acid metabolism, which could cause birth defects. If use cannot be avoided during the first trimester, then concurrent use of folinic acid is recommended. Patients should be warned of the possible risks, and alternative treatment should be undertaken when possible. There also is some indication that pyrimethamine reduces fertility rates, so patients expecting to become pregnant should be warned of this possibility.

    Breast-feeding

    Pyrimethamine is excreted into breast milk and the manufacturer recommends caution when administering it to breast-feeding women. However, previous American Academy of Pediatrics (AAP) recommendations considered pyrimethamine as usually compatible with breast-feeding. Pyrimethamine milk concentrations have been reported to range from 0.2 to 0.255 mcg/L at 6 hours after the dose, from 0.125 to 0.155 mcg/L at 24 hours after the dose, and from 0.095 to 0.0105 mcg/L at 48 hours after the dose.

    Geriatric

    Clinical studies of pyrimethamine did not include sufficient numbers of geriatric patients (age >= 65 years) to determine whether they respond differently from younger patients. 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.

    ADVERSE REACTIONS

    Severe

    eosinophilic pneumonia / Delayed / 0-1.0
    pancytopenia / Delayed / Incidence not known
    megaloblastic anemia / Delayed / Incidence not known
    Stevens-Johnson syndrome / Delayed / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    erythema multiforme / Delayed / Incidence not known
    acute generalized exanthematous pustulosis (AGEP) / Delayed / Incidence not known
    vasculitis / Delayed / Incidence not known
    toxic epidermal necrolysis / Delayed / Incidence not known

    Moderate

    thrombocytopenia / Delayed / Incidence not known
    glossitis / Early / Incidence not known
    hematuria / Delayed / Incidence not known
    leukopenia / Delayed / Incidence not known
    neutropenia / Delayed / Incidence not known

    Mild

    fever / Early / Incidence not known
    purpura / Delayed / Incidence not known
    rash (unspecified) / Early / Incidence not known
    vomiting / Early / Incidence not known
    anorexia / Delayed / Incidence not known

    DRUG INTERACTIONS

    Abacavir; Lamivudine, 3TC; Zidovudine, ZDV: (Major) Pyrimethamine should be used cautiously with zidovudine, ZDV because of the potential for the development of blood dyscrasias including megaloblastic anemia, agranulocytosis, or thrombocytopenia. Monitor CBCs routinely in patients receiving both drugs simultaneously; if signs of folate deficiency develop, pyrimethamine should be discontinued.
    Artemether; Lumefantrine: (Moderate) Other antimalarial agents, such as pyrimethamine, should not be given with artemether; lumefantrine unless there is no other treatment option because limited safety data are available.
    Azelaic Acid; Copper; Folic Acid; Nicotinamide; Pyridoxine; Zinc: (Moderate) L-methylfolate and pyrimethamine should be used together cautiously. Pyrimethamine is a folate antagonist. Plasma concentrations of both medications may be reduced when used concomitantly. (Moderate) Pyrimethamine is a folate antagonist. Some evidence suggests that administration of folic acid to leukemia patients receiving pyrimethamine for Pneumocystis carinii resulted in exacerbation of leukemia symptoms. Folic acid, vitamin B9 reportedly interferes with the action of pyrimethamine in treating toxoplasmosis. Further study is needed to confirm these interactions.
    Carbamazepine: (Moderate) Pyrimethamine should be used cautiously in patients receiving carbamazepine, due to the potential for additive bone marrow/hematologic effects.
    Chlorpromazine: (Major) Pyrimethamine has been shown in one report to reduce the hepatic metabolism of chlorpromazine, with markedly increased plasma concentrations of chlorpromazine and the 7-OH-chlorpromazine metabolite. Patients who are on stable chlorpromazine regimens should be monitored for increased phenothiazine effects if antimalarials, such as pyrimethamine, are added.
    Dapsone: (Major) Agranulocytosis has been reported in the second to third month of weekly concomitant treatment with dapsone and other hemolytic agents, such as pyrimethamine. This combination can increase the likelihood of adverse hematologic events.
    Diclofenac: (Moderate) Pyrimethamine is a folate antagonist. Some evidence suggests that administration of folic acid to leukemia patients receiving pyrimethamine for Pneumocystis carinii resulted in exacerbation of leukemia symptoms. Folic acid, vitamin B9 reportedly interferes with the action of pyrimethamine in treating toxoplasmosis. Further study is needed to confirm these interactions.
    Drospirenone; Ethinyl Estradiol; Levomefolate: (Moderate) L-methylfolate and pyrimethamine should be used together cautiously. Pyrimethamine is a folate antagonist. Plasma concentrations of both medications may be reduced when used concomitantly.
    Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate: (Moderate) L-methylfolate and pyrimethamine should be used together cautiously. Pyrimethamine is a folate antagonist. Plasma concentrations of both medications may be reduced when used concomitantly. (Moderate) Pyrimethamine is a folate antagonist. Some evidence suggests that administration of folic acid to leukemia patients receiving pyrimethamine for Pneumocystis carinii resulted in exacerbation of leukemia symptoms. Folic acid, vitamin B9 reportedly interferes with the action of pyrimethamine in treating toxoplasmosis. Further study is needed to confirm these interactions.
    Fluorouracil, 5-FU: (Major) Pyrimethamine should be used cautiously with other folate antagonists, such as fluorouracil, 5-FU, or agents that cause bone marrow suppression because of the potential for the development of blood dyscrasias including megaloblastic anemia, agranulocytosis, or thrombocytopenia. CBCs should be monitored routinely in patients receiving both drugs simultaneously.
    Folic Acid, Vitamin B9: (Moderate) L-methylfolate and pyrimethamine should be used together cautiously. Pyrimethamine is a folate antagonist. Plasma concentrations of both medications may be reduced when used concomitantly. (Moderate) Pyrimethamine is a folate antagonist. Some evidence suggests that administration of folic acid to leukemia patients receiving pyrimethamine for Pneumocystis carinii resulted in exacerbation of leukemia symptoms. Folic acid, vitamin B9 reportedly interferes with the action of pyrimethamine in treating toxoplasmosis. Further study is needed to confirm these interactions.
    Iron Salts: (Moderate) Pyrimethamine is a folate antagonist. Some evidence suggests that administration of folic acid to leukemia patients receiving pyrimethamine for Pneumocystis carinii resulted in exacerbation of leukemia symptoms. Folic acid, vitamin B9 reportedly interferes with the action of pyrimethamine in treating toxoplasmosis. Further study is needed to confirm these interactions.
    Lamivudine, 3TC; Zidovudine, ZDV: (Major) Pyrimethamine should be used cautiously with zidovudine, ZDV because of the potential for the development of blood dyscrasias including megaloblastic anemia, agranulocytosis, or thrombocytopenia. Monitor CBCs routinely in patients receiving both drugs simultaneously; if signs of folate deficiency develop, pyrimethamine should be discontinued.
    Lamotrigine: (Moderate) Lamotrigine inhibits dihydrofolate reductase. Caution should be exercised when administering pyrimethamine, which also inhibits this enzyme.
    Levomefolate: (Moderate) L-methylfolate and pyrimethamine should be used together cautiously. Pyrimethamine is a folate antagonist. Plasma concentrations of both medications may be reduced when used concomitantly.
    Levomefolate; Mecobalamin; Pyridoxal-5-phosphate: (Moderate) L-methylfolate and pyrimethamine should be used together cautiously. Pyrimethamine is a folate antagonist. Plasma concentrations of both medications may be reduced when used concomitantly.
    Lorazepam: (Moderate) Mild hepatotoxicity has been reported when pyrimethamine was coadministered with lorazepam.
    Methotrexate: (Major) Drugs with similar pharmacologic activity, such as pyrimethamine, may lead to additive antifolate effects and bone marrow suppression when used with methotrexate. Concurrent use of pemetrexed and methotrexate is unlikely, however, the combination should be avoided.
    Penicillamine: (Severe) Antimalarials have adverse reactions similar to those of penicillamine. Concomitant use is contraindicated because of the increased risk of developing severe hematologic and renal toxicity.
    Rabies Vaccine: (Major) If administered concurrently, antimalarials can impair the immunologic response to the rabies vaccine, thereby, decreasing its protective effect. If possible, administration of antimalarials should be avoided during use of the rabies vaccine for postexposure prophylaxis. When antimalarials must be administered to persons also receiving the rabies vaccine for postexposure prophylaxis, a serum rabies antibody titer should be obtained on day 14 (day of the 4th vaccination) to ensure an acceptable antibody response has been induced.
    Sapropterin: (Moderate) Drugs that inhibit folate metabolism, such as pyrimethamine, should be used with caution in patients taking sapropterin. For example, methotrexate has been shown to decrease endogenous tetrahydrobiopterin (BH4) concentrations by inhibiting the enzyme dihydropteridine reductase; a similar reaction could be expected in patients receiving pyrimethamine. Reduction of BH4 could make management of hyperphenylalaninemia with sapropterin more difficult. Folic acid supplementation has been shown to decrease the toxicity of pyrimethamine. Careful monitoring of blood phenylalanine concentrations is warranted in patients receiving these agents concurrently.
    Sulfamethoxazole; Trimethoprim, SMX-TMP, Cotrimoxazole: (Major) Use of other folate antagonists should be avoided during therapy with trimethoprim. Hematologic toxicity can be increased by concurrent use of pyrimethamine.
    Sulfonamides: (Major) The combination of pyrimethamine with sulfonamides can be synergistic against susceptible organisms, however, bone marrow suppression may be more likely to occur with combination therapy. CBCs should be monitored routinely in patients receiving both drugs simultaneously. Some references suggest routinely administering leucovorin during therapy with pyrimethamine even when used without any of the above drugs.
    Trimethoprim: (Major) Use of other folate antagonists should be avoided during therapy with trimethoprim. Hematologic toxicity can be increased by concurrent use of pyrimethamine.
    Trimetrexate: (Major) Pyrimethamine should be used cautiously with other folate antagonists, like trimetrexate, because of the potential for the development of blood dyscrasias including megaloblastic anemia, agranulocytosis, or thrombocytopenia.
    Zidovudine, ZDV: (Major) Pyrimethamine should be used cautiously with zidovudine, ZDV because of the potential for the development of blood dyscrasias including megaloblastic anemia, agranulocytosis, or thrombocytopenia. Monitor CBCs routinely in patients receiving both drugs simultaneously; if signs of folate deficiency develop, pyrimethamine should be discontinued.

    PREGNANCY AND LACTATION

    Pregnancy

    Pyrimethamine is classified as pregnancy category C. Pyrimethamine alone, or in combination with a sulfonamide, should be used with extreme caution during pregnancy. Use in the first 14—16 weeks is not recommended because of possible interference in folic acid metabolism, which could cause birth defects. If use cannot be avoided during the first trimester, then concurrent use of folinic acid is recommended. Patients should be warned of the possible risks, and alternative treatment should be undertaken when possible. There also is some indication that pyrimethamine reduces fertility rates, so patients expecting to become pregnant should be warned of this possibility.

    Pyrimethamine is excreted into breast milk and the manufacturer recommends caution when administering it to breast-feeding women. However, previous American Academy of Pediatrics (AAP) recommendations considered pyrimethamine as usually compatible with breast-feeding. Pyrimethamine milk concentrations have been reported to range from 0.2 to 0.255 mcg/L at 6 hours after the dose, from 0.125 to 0.155 mcg/L at 24 hours after the dose, and from 0.095 to 0.0105 mcg/L at 48 hours after the dose.

    MECHANISM OF ACTION

    Pyrimethamine is a folic acid antagonist. Its therapeutic activity is based on the differential requirement between host and parasite for nucleic acid precursors involved in growth. This activity is highly selective against Toxoplasma gondii. The action of pyrimethamine is greatly enhanced when used in conjunction with sulfonamides.

    PHARMACOKINETICS

    Pyrimethamine is administered orally. Protein binding of pyrimethamine ranges from 80—87%. Distribution is mainly into kidneys, lungs, liver, and spleen, with concentrations in blood cells. The drug crosses the placenta and is distributed into breast milk. Metabolism produces several unidentified metabolites. The half-life of pyrimethamine is between 80—123 hours, but it can be as low as 23 hours in AIDS patients, which may be due to changes in hepatic function or altered metabolism of the drug. Pyrimethamine and its metabolites are excreted in the urine; urinary excretion can persist for 30 days.

    Oral Route

    Following oral administration, pyrimethamine is rapidly absorbed from the GI tract, with peak serum concentrations being achieved in 2—6 hours.