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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 Pneumocystis pneumonia (PCP) prophylaxis†.
    For primary PCP prophylaxis in HIV-infected patients†.
    Oral dosage
    Adults

    50 or 75 mg PO once weekly plus leucovorin in combination with dapsone or 25 mg PO once daily plus leucovorin in combination with atovaquone as alternative therapy. Recommended for patients with CD4 count less than 200 cells/mm3, CD4 less than 14%, or CD4 count of 200 to 250 cells/mm3 if antiretroviral therapy (ART) initiation must be delayed and if CD4 count monitoring every 3 months is not possible. May discontinue if the CD4 count is 200 cells/mm3 or more for more than 3 months in response to ART or if the CD4 count is 100 to 200 cells/mm3 and HIV RNA remains below the limit of detection for 3 to 6 months. Restart prophylaxis if CD4 count is less than 100 cells/mm3 or CD4 count is 100 to 200 cells/mm3 and HIV RNA is above detection limit.

    Adolescents

    50 or 75 mg PO once weekly plus leucovorin in combination with dapsone or 25 mg PO once daily plus leucovorin in combination with atovaquone as alternative therapy. Recommended for patients with CD4 count less than 200 cells/mm3, CD4 less than 14%, or CD4 count of 200 to 250 cells/mm3 if antiretroviral therapy (ART) initiation must be delayed and if CD4 count monitoring every 3 months is not possible. May discontinue if the CD4 count is 200 cells/mm3 or more for more than 3 months in response to ART or if the CD4 count is 100 to 200 cells/mm3 and HIV RNA remains below the limit of detection for 3 to 6 months. Restart prophylaxis if CD4 count is less than 100 cells/mm3 or CD4 count is 100 to 200 cells/mm3 and HIV RNA is above detection limit.

    For secondary PCP prophylaxis (i.e., long-term suppressive therapy) in HIV-infected patients†.
    Oral dosage
    Adults

    50 or 75 mg PO once weekly plus leucovorin in combination with dapsone or 25 mg PO once daily plus leucovorin in combination with atovaquone as alternative therapy. May discontinue if the CD4 count is more than 200 cells/mm3 for more than 3 months in response to antiretroviral therapy (ART) or if the CD4 count is 100 to 200 cells/mm3 and HIV RNA remains below the limit of detection for 3 to 6 months. Restart prophylaxis if CD4 count is less than 100 cells/mm3 or CD4 count is 100 to 200 cells/mm3 and HIV RNA is above detection limit. If PCP is diagnosed or recurs at a CD4 count of more than 200 cells/mm3, lifelong prophylaxis is necessary.

    Adolescents

    50 or 75 mg PO once weekly plus leucovorin in combination with dapsone or 25 mg PO once daily plus leucovorin in combination with atovaquone as alternative therapy. May discontinue if the CD4 count is more than 200 cells/mm3 for more than 3 months in response to antiretroviral therapy (ART) or if the CD4 count is 100 to 200 cells/mm3 and HIV RNA remains below the limit of detection for 3 to 6 months. Restart prophylaxis if CD4 count is less than 100 cells/mm3 or CD4 count is 100 to 200 cells/mm3 and HIV RNA is above detection limit. If PCP is diagnosed or recurs at a CD4 count of more than 200 cells/mm3, lifelong prophylaxis is necessary.

    For primary PCP prophylaxis in hematopoietic stem cell transplant (HSCT) recipients†.
    Oral dosage
    Adults

    50 or 75 mg PO once weekly plus leucovorin in combination with dapsone or atovaquone starting at engraftment or 1 to 2 weeks before HSCT and continuing for at least 6 months after HSCT as alternative therapy. Recommended for all allogenic HSCT recipients and autologous HSCT recipients with underlying hematologic malignancies, those receiving intense conditioning therapy or graft manipulation, or those who have received purine analogs. Longer-term prophylaxis is recommended for the duration of immunosuppression for all patients who are receiving immunosuppressive therapy or have chronic graft-versus-host disease.

    For PCP prophylaxis in solid organ transplant recipients†.
    Oral dosage
    Adults

    15 mg PO once daily or 3 times weekly in combination with clindamycin for 3 to 6 months after kidney transplant, for at least 6 to 12 months after other transplants, as well as for at least 6 weeks during and after antirejection therapy in kidney transplant recipients, as alternative therapy. Lifelong prophylaxis is recommended for lung and small bowel transplant recipients, as well as patients with a history of prior PCP or chronic cytomegalovirus disease.

    For primary PCP prophylaxis in patients with cancer-related immunosuppression and hematological malignancies†.
    Oral dosage
    Adults

    50 or 75 mg PO once weekly plus leucovorin in combination with dapsone or atovaquone as alternative therapy. Recommended for patients receiving alemtuzumab, fludarabine/cyclophosphamide/rituximab, corticosteroids at doses equivalent to more than 20 mg/day of prednisone for 4 weeks, nucleoside or purine analogs, radiotherapy for brain tumors/metastasis plus high-dose steroids as well as for patients with acute lymphoblastic leukemia (ALL) and lymphoma treated with R-CHOP14 or escalated BEACOPP. Duration of prophylaxis for ALL is from induction to the end of maintenance. Prophylaxis for alemtuzumab-associated treatment and fludarabine/cyclophosphamide/rituximab treatment is suggested for at least 6 months after treatment completion.

    For the treatment of cystoisosporiasis†.
    For the treatment of cystoisosporiasis† in persons without HIV.
    Oral dosage
    Adults

    50 to 75 mg/day PO once daily or divided twice daily plus leucovorin for 7 days as an alternative.

    For the treatment of cystoisosporiasis† in persons with HIV.
    Oral dosage
    Adults

    50 to 75 mg/day PO once daily or divided twice daily plus leucovorin for 7 days as an alternative then chronic suppressive therapy. 

    Adolescents

    50 to 75 mg/day PO once daily or divided twice daily plus leucovorin for 7 days as an alternative then chronic suppressive therapy. 

    Infants and Children

    1 mg/kg/dose (Max: 25 mg/dose) PO once daily plus leucovorin for 14 days as an alternative then chronic suppressive therapy.

    For secondary cystoisosporiasis prophylaxis† (i.e., long-term suppressive therapy†) in persons with HIV.
    Oral dosage
    Adults

    25 mg PO once daily plus leucovorin in patients with CD4 count less than 200 cells/mm3 as an alternative. Discontinuation may be considered in patients without evidence of active infection who have sustained increase in CD4 count to more than 200 cells/mm3 for more than 6 months in response to antiretroviral therapy.

    Adolescents

    25 mg PO once daily plus leucovorin in patients with CD4 count less than 200 cells/mm3 as an alternative. Discontinuation may be considered in patients without evidence of active infection who have sustained increase in CD4 count to more than 200 cells/mm3 for more than 6 months in response to antiretroviral therapy.

    Infants and Children

    1 mg/kg/dose (Max: 25 mg/dose) PO once daily plus leucovorin in patients with severe immunosuppression (CDC immunologic category 3) as an alternative. Discontinuation may be considered in patients without evidence of active infection who have sustained improvement in immunologic status (CDC immunologic category 1 or 2) for more than 6 months in response to antiretroviral therapy.

    †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

    Use pyrimethamine during pregnancy only if the potential benefit justifies the risk to the fetus. Concurrent administration of folinic acid (leucovorin) is strongly recommended when pyrimethamine is used during pregnancy. There are no adequate and well-controlled studies of pyrimethamine use in pregnant women. Pyrimethamine has been shown to be teratogenic in rats when given in oral doses 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 5 times the human dose for the treatment of toxoplasmosis.

    Breast-feeding

    Pyrimethamine is excreted in breast milk. Because of the potential for serous adverse reactions in nursing infants, discontinue nursing or discontinue pyrimethamine, taking into account the importance of the drug to the mother. 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.

    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 / 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.
    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.
    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) 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.
    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: (Major) Do not use penicillamine concurrently with antimalarials due to an increased risk of severe hematologic and renal adverse reactions.
    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.
    Sulfadiazine: (Moderate) Concomitant use of other antifolic drugs associated with myelosuppression, including sulfonamides, may increase the risk of bone marrow suppression.
    Sulfamethoxazole; Trimethoprim, SMX-TMP, Cotrimoxazole: (Major) Avoid concurrent use of sulfamethoxazole and pyrimethamine. Reports suggest that patients receiving pyrimethamine as malaria prophylaxis in doses more than 25 mg/week may develop megaloblastic anemia with concurrent sulfamethoxazole; trimethoprim. Additionally, the concomitant use of other antifolic drugs associated with myelosuppression, including sulfamethoxazole; trimethoprim, may increase the risk of bone marrow suppression. (Major) Avoid concurrent use of trimethoprim and pyrimethamine. Reports suggest that patients receiving pyrimethamine as malaria prophylaxis in doses more than 25 mg/week may develop megaloblastic anemia with concurrent sulfamethoxazole; trimethoprim. Additionally, the concomitant use of other antifolic drugs associated with myelosuppression, including sulfamethoxazole; trimethoprim, may increase the risk of bone marrow suppression.
    Sulfasalazine: (Moderate) Concomitant use of other antifolic drugs associated with myelosuppression, including sulfonamides, may increase the risk of bone marrow suppression.
    Trimethoprim: (Major) Avoid concurrent use of trimethoprim and pyrimethamine. Reports suggest that patients receiving pyrimethamine as malaria prophylaxis in doses more than 25 mg/week may develop megaloblastic anemia with concurrent sulfamethoxazole; trimethoprim. Additionally, the concomitant use of other antifolic drugs associated with myelosuppression, including sulfamethoxazole; trimethoprim, may increase the risk of bone marrow suppression.
    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

    Use pyrimethamine during pregnancy only if the potential benefit justifies the risk to the fetus. Concurrent administration of folinic acid (leucovorin) is strongly recommended when pyrimethamine is used during pregnancy. There are no adequate and well-controlled studies of pyrimethamine use in pregnant women. Pyrimethamine has been shown to be teratogenic in rats when given in oral doses 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 5 times the human dose for the treatment of toxoplasmosis.

    Pyrimethamine is excreted in breast milk. Because of the potential for serous adverse reactions in nursing infants, discontinue nursing or discontinue pyrimethamine, taking into account the importance of the drug to the mother. 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.