VA Class:AP101

AHFS Class:

• Antimalarials 8:30.08

Generic Name(s):

• Pyrimethamine

Pyrimethamine, a folic acid antagonist anti-infective, is used as an antimalarial and antiprotozoal agent.125,161,167

Malaria

Pyrimethamine has been used in the past for prevention or chemoprophylaxis of malaria caused by susceptible Plasmodium ; however, pyrimethamine-resistant strains are prevalent worldwide and the drug is not suitable for prevention of malaria in most areas.167 Pyrimethamine is not included in US Centers for Disease Control and Prevention (CDC) recommendations for the prevention of malaria.115

Pyrimethamine has been used in the past for the treatment of acute uncomplicated malaria;167 however, pyrimethamine-resistant strains are prevalent worldwide and the drug should not be used alone for the treatment of malaria.161,167 Pyrimethamine is not included in CDC recommendations for the treatment of malaria.143

A fixed-combination preparation containing sulfadoxine and pyrimethamine (sulfadoxine/pyrimethamine; Fansidar^®) has been used for prevention or chemoprophylaxis of malaria and for the treatment of acute uncomplicated malaria caused by chloroquine-resistant P. falciparum .128,139,168,188,189 However, resistance to sulfadoxine/pyrimethamine is widespread (e.g., Amazon River Basin area of South America, much of Southeast Asia, other parts of Asia, large parts of Africa)44,45,115,126,127,128,160,161 and severe and sometimes fatal adverse reactions have been reported when once-weekly regimens of the fixed combination were used for prevention of malaria (see Cautions: Dermatologic and Sensitivity Reactions).111,112,113,114,132,139,144,145,168 The fixed-combination preparation is no longer commercially available in the US and is not included in CDC recommendations for prevention or treatment of malaria.115,143 Sulfadoxine/pyrimethamine may still be used for the treatment of uncomplicated P. falciparum malaria in some countries where the disease is endemic,161 usually in conjunction with artesunate in artemisinin-based combination therapy (ACT).161

Information on the risk of malaria transmission in specific countries, information on mosquito avoidance measures, recommendations regarding whether chemoprophylaxis of malaria is indicated, and information on the choice of antimalarials for prevention of malaria are available from the CDC at [Web] and [Web].115

Assistance with diagnosis or treatment of malaria is available by contacting the CDC Malaria Hotline at 770-488-7788 or 855-856-4713 from 9:00 a.m. to 5:00 p.m. Eastern Standard Time or the CDC Emergency Operation Center at 770-488-7100 after hours and on weekends and holidays.143,144

Toxoplasmosis

Pyrimethamine (with leucovorin) is used in conjunction with sulfadiazine or, alternatively, clindamycin, atovaquone, or azithromycin for the treatment of toxoplasmosis caused by Toxoplasma gondii .134,155,156,167,184,185 In addition, in individuals with human immunodeficiency virus (HIV) infection, pyrimethamine (with leucovorin) is used in conjunction with dapsone or atovaquone for prevention of initial episodes of toxoplasmosis (primary prophylaxis)† or in conjunction with sulfadiazine, atovaquone, or clindamycin for chronic maintenance therapy to prevent relapse of toxoplasmosis (secondary prophylaxis)†.134,155,156,178,195,210,211 Leucovorin is used with pyrimethamine in these regimens to prevent pyrimethamine-induced adverse hematologic effects.134,155,156,184,185,198

Treatment

The CDC, National Institutes of Health (NIH), HIV Medicine Association of the Infectious Diseases Society of America (IDSA), American Academy of Pediatrics (AAP), and others state that a regimen of pyrimethamine (and leucovorin) in conjunction with sulfadiazine is the regimen of choice for initial treatment of toxoplasmosis, including toxoplasmosis in HIV-infected adults, adolescents, and children.134,155,156

A regimen of pyrimethamine (and leucovorin) in conjunction with clindamycin has been used with some success for the treatment of toxoplasmosis in immunocompromised patients (e.g., HIV-infected individuals)134,152,153,154,155,156,164,184,193,194,198 and is the preferred alternative in HIV-infected adults and adolescents who are unable to tolerate the regimen of choice (pyrimethamine and leucovorin in conjunction with sulfadiazine) or who failed to respond to or relapsed with such therapy.155 Although relative efficacy has not been determined, other alternative regimens that have been used for treatment of toxoplasmosis in HIV-infected adults and adolescents include pyrimethamine (and leucovorin) in conjunction with atovaquone, atovaquone alone or in conjunction with sulfadiazine, pyrimethamine (and leucovorin) in conjunction with azithromycin, or co-trimoxazole.155 When a parenteral regimen is required for initial treatment of toxoplasmosis in severely ill adults or adolescents, some experts suggest parenteral co-trimoxazole or a regimen of oral pyrimethamine (and leucovorin) in conjunction with parenteral clindamycin.155

Pregnant HIV-infected women with suspected or confirmed primary T. gondii infection should be managed in consultation with a specialist in maternal-fetal medicine or other appropriate specialists.155,156 The CDC, NIH, and IDSA state that, despite concerns about use of pyrimethamine in pregnant women (see Pregnancy under Cautions: Pregnancy, Fertility, and Lactation), treatment of toxoplasmosis in pregnant women generally should be the same as that in nonpregnant adults.155 Some clinicians state that spiramycin (not commercially available in the US) can be used as an alternative to pyrimethamine regimens for the treatment of toxoplasmosis in pregnant women, especially during the first trimester.134

Pyrimethamine (and leucovorin) in conjunction with sulfadiazine also is the regimen of choice for treatment of congenital toxoplasmosis and for treatment of acquired CNS, ocular, or systemic toxoplasmosis in HIV-infected children.156 The preferred alternative for treatment of toxoplasmosis in neonates and HIV-infected children with sulfonamide sensitivity is pyrimethamine (and leucovorin) in conjunction with clindamycin;156 other alternative regimens that have been used in adults and adolescents have not been adequately studied in children.156 Empiric treatment of congenital toxoplasmosis should be strongly considered in infants born to HIV-infected women who had symptomatic or asymptomatic toxoplasmosis during pregnancy, regardless of whether the mother received toxoplasmosis treatment during the pregnancy.156

Prevention

Primary Prophylaxis

The CDC, NIH, and IDSA recommend primary prophylaxis against T. gondii encephalitis in all HIV-infected adults and adolescents who are seropositive for Toxoplasma IgG antibody and have CD4⁺ T-cell counts less than 100/mm³.155 Although specific levels of immunosuppression that increase the risk for T. gondii encephalitis in HIV-infected children are less well defined, the CDC, NIH, IDSA, and AAP recommend primary prophylaxis against Toxoplasma encephalitis in toxoplasma-seropositive children younger than 6 years of age who have CD4⁺ T-cell percentages less than 15% and in HIV-infected children 6 years of age or older who have CD4⁺ T-cell counts less than 100/mm³.156

Co-trimoxazole is the drug of choice for primary prophylaxis against toxoplasmosis in HIV-infected adults, adolescents, and children.155,156 A regimen of pyrimethamine (and leucovorin) used in conjunction with dapsone is the recommended alternative for primary prophylaxis against toxoplasmosis† in HIV-infected adults or adolescents who cannot tolerate co-trimoxazole.155 (See Drug Interactions: Dapsone.) A regimen of atovaquone with or without pyrimethamine (and leucovorin) also may be considered an alternative regimen for primary prophylaxis in HIV-infected adults or adolescents who cannot tolerate co-trimoxazole.134,155 In HIV-infected children who cannot tolerate co-trimoxazole, a regimen of pyrimethamine (and leucovorin) used in conjunction with dapsone can be used as an alternative for primary prophylaxis in those 1 month of age or older and a regimen of pyrimethamine (and leucovorin) used in conjunction with atovaquone can be used as an alternative in those 4-24 months of age.156

The CDC, NIH, and IDSA state that primary prophylaxis against toxoplasmosis generally can be discontinued in HIV-infected adults and adolescents who have CD4⁺ T-cell counts that have remained greater than 200/mm³ for longer than 3 months in response to antiretroviral therapy.155 Discontinuance of primary prophylaxis is recommended in adults and adolescents meeting this criterion since prophylaxis in these patients appears to add little benefit in terms of toxoplasmosis disease prevention and discontinuance will reduce the medication burden, the potential for toxicity, drug interactions, selection of drug-resistant pathogens, and cost.155 However, primary prophylaxis against toxoplasmosis should be reinitiated in HIV-infected adults and adolescents if CD4⁺ T-cell counts decrease to less than 100-200/mm³.155

The safety of discontinuing primary prophylaxis against toxoplasmosis in HIV-infected children whose immunologic status improves on antiretroviral therapy has not been extensively studied.156 The CDC, NIH, IDSA, and AAP state that primary prophylaxis against toxoplasmosis should not be discontinued in HIV-infected children younger than 1 year of age.156 However, based on data from adults, these experts state that discontinuance of primary prophylaxis can be considered in HIV-infected children 1 to less than 6 years of age who have received at least 6 months of antiretroviral therapy and have CD4⁺ T-cell percentages of 15% or greater that have been sustained for longer than 3 months.156 In HIV-infected children 6 years of age or older who have received at least 6 months of antiretroviral therapy, primary prophylaxis against toxoplasmosis can be discontinued if CD4⁺ T-cell counts have remained greater than 200/mm³ for longer than 3 months.156 Primary prophylaxis against toxoplasmosis should be reinitiated if CD4⁺ T-cell percentages decrease to less than 15% in HIV-infected children younger than 6 years of age or if CD4⁺ T-cell counts decrease to less than 100-200/mm³ in HIV-infected children 6 years of age or older.156

Prevention of Recurrence

The CDC, NIH, IDSA, and AAP recommend that HIV-infected adults, adolescents, and children who have completed initial treatment of T. gondii encephalitis receive chronic maintenance therapy (secondary prophylaxis) to prevent relapse.155,156

A regimen of pyrimethamine (and leucovorin) in conjunction with sulfadiazine usually is the regimen of choice for secondary prophylaxis† of toxoplasmosis in HIV-infected adults, adolescents, and children since it provides coverage against both toxoplasmosis and Pneumocystis jiroveci (formerly Pneumocystis carinii ) pneumonia (PCP).155,156 Alternatively, a regimen of pyrimethamine (and leucovorin) in conjunction with clindamycin or a regimen of atovaquone with or without pyrimethamine (and leucovorin) can be used as an alternative for secondary prophylaxis of toxoplasmosis in HIV-infected adults, adolescents, and children who cannot tolerate sulfonamides.155,156 Limited data indicate that co-trimoxazole may be another effective alternative for secondary prophylaxis against toxoplasmosis in HIV-infected individuals,155,156 but is recommended in children only when pyrimethamine regimens are not tolerated.156

The CDC, NIH, and IDSA state that secondary prophylaxis against toxoplasmosis generally can be discontinued in HIV-infected adults and adolescents who have successfully completed initial therapy for toxoplasmic encephalitis, remain asymptomatic with respect to toxoplasmic encephalitis, and have CD4⁺ T-cell counts that have remained greater than 200/mm³ for more than 6 months in response to antiretroviral therapy since limited data indicate such individuals are at low risk for recurrence of toxoplasmic encephalitis.155 Some experts would obtain a magnetic resonance image of the brain as part of their evaluation to determine whether discontinuance of secondary prophylaxis is appropriate.155 Secondary prophylaxis against toxoplasmosis should be reinitiated in HIV-infected adults and adolescents if CD4⁺ T-cell counts decrease to less than 200/mm³.155

The safety of discontinuing secondary toxoplasmosis prophylaxis in HIV-infected children receiving potent antiretroviral therapy has not been extensively studied.156 However, based on data from adults, the CDC, NIH, IDSA, and AAP state that discontinuance of secondary prophylaxis against toxoplasmosis can be considered in HIV-infected children 1 to less than 6 years of age can consider discontinuing secondary prophylaxis against T. gondii after toxoplasmosis treatment has been completed and more than 6 months of stable antiretroviral therapy has been given, provided the child is asymptomatic and the CD4⁺ T-cell percentages have remained greater than 15% for more than 6 consecutive months.156 In HIV-infected children 6 years of age or older who have received more than 6 months of antiretroviral therapy, consideration can be given to discontinuing secondary prophylaxis against toxoplasmosis if CD4⁺ T-cell counts have remained greater than 200/mm³ for more than 6 consecutive months.156 Prophylaxis should be reinitiated in HIV-infected children if these parameters are not met.156

Cystoisosporiasis

Although co-trimoxazole is the drug of choice for the treatment of GI infections caused by Cystoisospora belli (formerly Isospora belli ),134,155,156 pyrimethamine has been used for the treatment of cystoisosporiasis† (formerly isosporiasis) in some patients (e.g., HIV-infected patients) when co-trimoxazole was not tolerated or could not be used.134,155,156,192

The CDC, NIH, IDSA, and AAP recommend a regimen of pyrimethamine (and leucovorin) as the preferred alternative to co-trimoxazole for the treatment of acute C. belli infections† in HIV-infected adults, adolescents, and children who fail to respond to or cannot tolerate co-trimoxazole.155,156 These experts also recommend a regimen of pyrimethamine (and leucovorin) as the preferred alternative to co-trimoxazole for chronic maintenance therapy (secondary prophylaxis) of cystoisosporiasis† in HIV-infected adults, adolescents, and children who cannot tolerate co-trimoxazole.155,156

Pneumocystis jiroveci Pneumonia

Prevention

Primary and Secondary Prophylaxis

Pyrimethamine (with leucovorin) has been used in conjunction with dapsone for primary or secondary prophylaxis of Pneumocystis jiroveci (formerly Pneumocystis carinii ) pneumonia† (PCP).134,155,171,173,174,175,176,177,178,179 (See Drug Interactions: Dapsone.)

The CDC, NIH, and IDSA recommend primary prophylaxis against PCP in HIV-infected adults and adolescents with CD4⁺ T-cell counts less than 200/mm³ or a history of oropharyngeal candidiasis.155 Primary prophylaxis against PCP also should be considered if the CD4⁺ T-cell percentage is less than 14% or there is a history of an AIDS-defining illness.155

Co-trimoxazole generally is the drug of choice for prevention of initial episodes (primary prophylaxis) of PCP in HIV-infected adults, adolescents, and children and for chronic maintenance therapy to prevent recurrence following an initial PCP episode in these individuals (secondary prophylaxis).134,155,156

Alternative regimens that can be used for primary or secondary prophylaxis of PCP† in HIV-infected adults or adolescents who cannot tolerate co-trimoxazole include dapsone (with or without pyrimethamine and leucovorin), aerosolized pentamidine, or atovaquone (with or without pyrimethamine and leucovorin).134,155 In HIV-infected adults or adolescents who cannot receive co-trimoxazole and are seropositive for T. gondii , either the dapsone and pyrimethamine (and leucovorin) regimen or a regimen of atovaquone (with or without pyrimethamine and leucovorin) would provide prophylaxis against both PCP and toxoplasmosis.155

Pyrimethamine regimens are not included in CDC, NIH, IDSA, and AAP recommendations for primary or secondary prevention of PCP in HIV-infected children;156 alternative regimens for primary or secondary prophylaxis of PCP in HIV-infected children who cannot tolerate co-trimoxazole are dapsone, aerosolized pentamidine, or atovaquone.156

Administration

Pyrimethamine is administered orally.167

If anorexia or vomiting occur during pyrimethamine therapy, these adverse GI effects may be minimized by taking the drug with meals.167

For administration in children unable to swallow tablets whole, an oral suspension of pyrimethamine can be prepared by crushing pyrimethamine tablets and suspending the drug in water, cherry syrup, or sucrose-containing solutions.109 (See Chemistry and Stability: Stability.) These oral suspensions should be shaken prior to administration.109

Dosage

Malaria

Prevention

If pyrimethamine is used for prevention of malaria caused by susceptible Plasmodium , the manufacturer recommends a dosage of 25 mg once weekly in adults and children older than 10 years of age, 12.5 mg once weekly in children 4-10 years of age, and 6.25 mg once weekly in children younger than 4 years of age.167 Because pyrimethamine-resistant strains are prevalent worldwide, the drug is not suitable for prevention of malaria in most areas.167 (See Uses: Malaria.)

Treatment

If pyrimethamine is used for treatment of acute malaria, the manufacturer recommends that pyrimethamine be given in a dosage of 25 mg once daily for 2 days in conjunction with a sulfonamide to initiate transmission control and suppression of non-falciparum malaria.167 If pyrimethamine must be used alone in the treatment of acute malaria in semi-immune individuals, the manufacturer recommends that adults receive 50 mg daily for 2 days followed by 25 mg once weekly for at least 10 weeks and that children 4-10 years of age receive 25 mg once daily for 2 days followed by 12.5 mg once weekly for at least 10 weeks.167

Because pyrimethamine-resistant strains are prevalent worldwide, the drug should not be used alone for treatment of acute malaria.167 (See Uses: Malaria.)

Toxoplasmosis

Treatment

For the treatment of toxoplasmosis caused by Toxoplasma gondii , pyrimethamine (with leucovorin) is given in conjunction with sulfadiazine or, alternatively, clindamycin, atovaquone, or azithromycin.134,155,156,167,184,185 Because there is marked variation in tolerance to pyrimethamine at the high dosage used for the treatment of toxoplasmosis, dosage of the drug must be carefully adjusted to provide the maximum therapeutic effect with minimum adverse effects.167 In addition, leucovorin should be administered concomitantly to prevent pyrimethamine-induced adverse hematologic effects.134,155,156,167

The manufacturer states that the usual initial adult dosage of pyrimethamine for the treatment of toxoplasmosis is 50-75 mg daily.167 This initial adult dosage of pyrimethamine should be continued in conjunction with the usual dosage of a sulfonamide for 1-3 weeks, depending on the patient's response and tolerance; dosage of both pyrimethamine and the sulfonamide should then be reduced by 50% and continued for an additional 4-5 weeks.167 The manufacturer recommends that children receive an initial pyrimethamine dosage of 1 mg/kg daily in 2 divided doses given for 2-4 days and then dosage may be reduced by 50% and continued for approximately 1 month; a sulfonamide should be given concomitantly at the usual pediatric dosage.167

For the treatment of T. gondii encephalitis in adults and adolescents with human immunodeficiency virus (HIV) infection, the US Centers for Disease Control and Prevention (CDC), National Institutes of Health (NIH), and HIV Medicine Association of the Infectious Diseases Society of America (IDSA) recommend a 200-mg loading dose of pyrimethamine followed by 50 mg once daily (in those weighing less than 60 kg) or 75 mg once daily (in those weighing 60 kg or more) given in conjunction with oral leucovorin (10-25 mg once daily; may be increased to 50 mg once or twice daily) and oral sulfadiazine (1 g every 6 hours in those weighing less than 60 kg or 1.5 g every 6 hours in those weighing 60 kg or more).155 Alternatively, these experts state that this dosage of pyrimethamine and leucovorin may be used in conjunction with oral or IV clindamycin (600 mg every 6 hours), oral atovaquone (1.5 g twice daily), or oral azithromycin (0.9-1.2 g once daily).155 The treatment regimen should be continued for at least 6 weeks; a longer duration may be appropriate if clinical or radiologic disease is extensive or there is an incomplete response at 6 weeks.155

For the treatment of congenital toxoplasmosis, the CDC, NIH, IDSA, and American Academy of Pediatrics (AAP) recommend a pyrimethamine dosage of 2 mg/kg once daily for 2 days, followed by 1 mg/kg once daily for 2-6 months and then 1 mg/kg 3 times weekly; pyrimethamine is given in conjunction with oral or IM leucovorin (10 mg with each pyrimethamine dose) and oral sulfadiazine (50 mg/kg twice daily).156 The recommended duration of treatment for congenital toxoplasmosis in HIV-infected infants is 12 months.156

For the treatment of acquired CNS, ocular, or systemic toxoplasmosis in HIV-infected children, the CDC, NIH, IDSA, and AAP recommend a pyrimethamine dosage of 2 mg/kg (up to 50 mg) once daily for 3 days followed by 1 mg/kg (up to 25 mg) once daily; pyrimethamine is given in conjunction with oral leucovorin (10-25 mg once daily) and oral sulfadiazine (25-50 mg/kg [up to 1-1.5 g] 4 times daily).156 Alternatively, these experts state that this dosage of pyrimethamine and leucovorin can be given in conjunction with oral or IV clindamycin (5-7.5 mg/kg [up to 600 mg] 4 times daily).156 The treatment regimen should be continued for at least 6 weeks; a longer duration may be appropriate if the disease is extensive or the response is incomplete at 6 weeks.156

Primary Prophylaxis

When a regimen of pyrimethamine (and leucovorin) in conjunction with dapsone is used as an alternative to co-trimoxazole for primary prophylaxis against toxoplasmosis† in HIV-infected adults and adolescents who are seropositive for Toxoplasma IgG antibody and have CD4⁺ T-cell counts less than 100/mm³, the CDC, NIH, and IDSA recommend pyrimethamine 50 mg once weekly with oral leucovorin (25 mg once weekly) and dapsone (50 mg once daily).155 Alternatively, a regimen of pyrimethamine 75 mg, leucovorin 25 mg, and dapsone 200 mg can be given once weekly in adults and adolescents.155 When a regimen of pyrimethamine (and leucovorin) in conjunction with atovaquone is used for primary prophylaxis against toxoplasmosis in HIV-infected adults and adolescents, pyrimethamine 25 mg once daily with oral leucovorin (10 mg once daily) and atovaquone (1.5 g once daily) is recommended.155

When a regimen of pyrimethamine (and leucovorin) in conjunction with dapsone is used as an alternative to co-trimoxazole for primary prophylaxis against toxoplasmosis† in HIV-infected infants and children 1 month of age or older, the CDC, NIH, IDSA, and AAP recommend a pyrimethamine dosage of 1 mg/kg (up to 25 mg) once daily with oral leucovorin (5 mg once every 3 days) and oral dapsone (2 mg/kg or 15 mg/m² [up to 25 mg] once daily).156 When a regimen of pyrimethamine (and leucovorin) in conjunction with atovaquone is used as an alternative for primary prophylaxis against toxoplasmosis in those 4-24 months of age, pyrimethamine 1 mg/kg or 15 mg/m² (up to 25 mg) once daily with oral leucovorin (5 mg once every 3 days) and atovaquone (45 mg/kg once daily) is recommended.156

The CDC, NIH, and IDSA state that primary prophylaxis against toxoplasmosis generally can be discontinued in HIV-infected adults and adolescents who have CD4⁺ T-cell counts that have remained greater than 200/mm³ for longer than 3 months in response to antiretroviral therapy,155 but should be reinitiated if CD4⁺ T-cell counts decrease to less than 100-200/mm³.155 The safety of discontinuing primary prophylaxis against toxoplasmosis in HIV-infected children whose immunologic status improves on antiretroviral therapy has not been extensively studied.156 (See Primary Prophylaxis under Toxoplasmosis: Prevention, in Uses.)

Prevention of Recurrence

When a regimen of pyrimethamine (and leucovorin) in conjunction with sulfadiazine or clindamycin is used for chronic maintenance therapy (secondary prophylaxis) to prevent relapse of toxoplasmosis† in HIV-infected adults and adolescents, the CDC, NIH, and IDSA recommend pyrimethamine in a dosage of 25-50 mg once daily with oral leucovorin (10-25 mg once daily) and either oral sulfadiazine (2-4 g daily in 2-4 divided doses) or oral clindamycin (600 mg every 8 hours).155 When a regimen of pyrimethamine (and leucovorin) in conjunction with atovaquone is used for secondary prophylaxis to prevent relapse of toxoplasmosis in HIV-infected adults and adolescents, these experts recommend a pyrimethamine dosage of 25 mg once daily with oral leucovorin (10 mg once daily) and oral atovaquone (750-1500 mg twice daily).155

When a regimen of pyrimethamine (and leucovorin) in conjunction with sulfadiazine or clindamycin is used for secondary prophylaxis of toxoplasmosis† in HIV-infected infants and children, the CDC, NIH, IDSA, and AAP recommend a pyrimethamine dosage of 1 mg/kg or 15 mg/m² (up to 25 mg) once daily with oral leucovorin (5 mg once every 3 days) and either sulfadiazine (42.5-60 mg/kg twice daily [up to 2-4 g daily]) or clindamycin (7-10 mg/kg 3 times daily).156 When a regimen of pyrimethamine (and leucovorin) in conjunction with atovaquone is used as an alternative for secondary prophylaxis against toxoplasmosis in those 4-24 months of age, pyrimethamine 1 mg/kg or 15 mg/m² (up to 25 mg) once daily with oral leucovorin (5 mg once every 3 days) and atovaquone (45 mg/kg once daily) is recommended.156

The CDC, NIH, and IDSA state that secondary prophylaxis against toxoplasmosis generally can be discontinued in HIV-infected adults and adolescents who have successfully completed initial therapy for toxoplasmic encephalitis, remain asymptomatic with respect to toxoplasmic encephalitis, and have CD4⁺ T-cell counts that have remained greater than 200/mm³ for more than 6 months in response to antiretroviral therapy.155 The safety of discontinuing secondary prophylaxis against toxoplasmosis in HIV-infected children receiving antiretroviral therapy has not been extensively studied.156 (See Prevention of Recurrence under Toxoplasmosis: Prevention, in Uses.)

Cystoisosporiasis

Treatment

For the treatment of acute infections caused by Cystoisospora belli † (formerly Isospora belli ) in HIV-infected adults and adolescents who cannot tolerate co-trimoxazole, the CDC, NIH, and IDSA recommend that pyrimethamine be given in a dosage of 50-75 mg once daily with oral leucovorin (10-25 mg once daily).155

For the treatment of acute infections caused by C. belli † in HIV-infected children who cannot tolerate co-trimoxazole, the CDC, NIH, IDSA, and AAP recommend that pyrimethamine be given in a dosage of 1 mg/kg once daily with oral leucovorin (10-25 mg once daily) for 14 days.156

Secondary Prophylaxis

If pyrimethamine (with leucovorin) is used as an alternative to co-trimoxazole for chronic maintenance therapy (secondary prophylaxis) of cystoisosporiasis† in HIV-infected adults and adolescents with CD4⁺ T-cell counts less than 200/mm³, a pyrimethamine dosage of 25 mg once daily with oral leucovorin (5-10 mg once daily) is recommended.155

If used as an alternative for secondary prophylaxis of cystoisosporiasis† in HIV-infected children who cannot tolerate co-trimoxazole, pyrimethamine should be given in a dosage of 1 mg/kg (up to 25 mg) once daily with oral leucovorin (10-25 mg once daily).156

Consideration can be given to discontinuing secondary prophylaxis against cystoisosporiasis in HIV-infected adults and adolescents if CD4⁺ T-cell counts exceed 200/mm³ for more than 6 months in response to antiretroviral therapy and there is no evidence of active C. belli infection.155 In children receiving antiretroviral therapy, consideration can be given to discontinuing secondary prophylaxis against cystoisosporiasis if there is sustained improvement for more than 6 months in CD4⁺ T-cell counts or CD4 percentages (change from CDC immunologic category 3 to category 1 or 2).156

Pneumocystis jiroveci Pneumonia

Primary and Secondary Prophylaxis

When used in conjunction with dapsone for primary or secondary prophylaxis of Pneumocystis jiroveci (formerly Pneumocystis carinii ) pneumonia† (PCP) in HIV-infected adults or adolescents, the CDC, NIH, IDSA, and other clinicians recommend a pyrimethamine dosage of 50 mg once weekly with oral leucovorin (25 mg once weekly) in conjunction with dapsone (50 mg once daily).134,155 Alternatively, adults and adolescents may receive pyrimethamine 75 mg once weekly with oral leucovorin (25 mg once weekly) in conjunction with dapsone (200 mg once weekly).134,155

If used in conjunction with atovaquone as an alternative for primary or secondary prophylaxis of PCP† in HIV-infected adults or adolescents, the CDC, NIH, and IDSA recommend a pyrimethamine dosage of 25 mg once daily with oral leucovorin (10 mg once daily) in conjunction with atovaquone (1.5 g once daily).155

The CDC, NIH, and IDSA state that primary or secondary PCP prophylaxis generally can be discontinued in HIV-infected adults and adolescents if CD4⁺ T-cell counts have remained at 200/mm³ or greater for at least 3 months in response to antiretroviral therapy, but should be reinitiated if CD4⁺ T-cell counts decrease to less than 200/mm³.155 However, secondary prophylaxis probably should be continued for life (regardless of CD4⁺ T-cell count) if PCP was diagnosed or recurred when CD4⁺ T-cell counts were greater than 200/mm³.155

In dosages used for prophylaxis and treatment of malaria, adverse effects of pyrimethamine are usually infrequent. However, prolonged therapy with pyrimethamine and the high dosages of the drug required for the treatment of toxoplasmosis are associated with a high incidence of adverse hematologic effects that result from folic acid deficiency.125,167

Hematologic Effects

High dosages of pyrimethamine may deplete folic acid stores in patients receiving the drug and cause reversible bone marrow depression; this effect does not generally occur with dosages of pyrimethamine used in the prevention or treatment of malaria. Megaloblastic anemia, leukopenia, thrombocytopenia, and pancytopenia have been reported with high dosages of pyrimethamine used for the treatment of toxoplasmosis.125,167 Hematologic effects may also occur with lower dosages in certain individuals.167 Adverse hematologic effects, including megaloblastic anemia, generally are reversible following discontinuance of pyrimethamine and administration of leucovorin.125

GI Effects

Anorexia, abdominal cramps, diarrhea,167 and vomiting167 may occur with high dosages of pyrimethamine. Anorexia and vomiting may be minimized by reducing dosage of pyrimethamine or by administering the drug with meals.167 Atrophic glossitis or gastritis also has been reported with high dosages of pyrimethamine.167

Nervous System Effects

High dosages of pyrimethamine may result in adverse nervous system effects, including ataxia, tremors, and seizures, and less specific symptoms such as insomnia, depression, fatigue, malaise, headache, lightheadedness, and irritability.125

Dermatologic and Sensitivity Reactions

Sensitivity reactions, occasionally severe (e.g., Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, anaphylaxis) have been reported with pyrimethamine, especially when the drug was used with a sulfonamide.167

Severe, sometimes fatal, hypersensitivity reactions have occurred in patients receiving a fixed-combination preparation of sulfadoxine and pyrimethamine (sulfadoxine/pyrimethamine; Fansidar^®).110,111,112,114,128,132,136,139,140,143,144,145,159 In most reported cases, fatalities resulted from severe cutaneous reactions, including erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis.110,139,140,143,144,145,159 Pulmonary hypersensitivity reactions,111,138,140 a fatal reaction involving the skin, liver, and kidneys,112 and fatal hepatitis also have been reported in patients receiving the fixed combination.132 The fixed-combination preparation is no longer commercially available in the US,168 but may still be available in other countries.161

Other Adverse Effects

Disorders of cardiac rhythm,167 fever,125 hematuria,167 abnormal skin pigmentation,125 pulmonary eosinophilia,167 and hyperphenylalaninemia125,167 have been reported rarely in patients receiving pyrimethamine.

Precautions and Contraindications

Pyrimethamine is contraindicated in patients hypersensitive to the drug or any ingredient in the formulation.167

Pyrimethamine also is contraindicated in patients with megaloblastic anemia caused by folate deficiency.167

Pyrimethamine should be used with caution in patients with possible folate deficiency, including patients with malabsorption syndrome, alcoholism, pregnancy (see Pregnancy, Fertility, and Lactation), and those receiving other drugs that affect folate levels (e.g., sulfonamides, co-trimoxazole, trimethoprim, phenytoin).167 (See Drug Interactions.)

The recommended dosages of pyrimethamine should not be exceeded.167 Dosage of pyrimethamine required for the treatment of toxoplasmosis approaches the toxic level.167 Complete blood cell counts (CBCs), including platelet counts, should be performed twice weekly in patients receiving pyrimethamine in high dosage.167 When pyrimethamine is used for the treatment of toxoplasmosis, a small staring dosage is recommended in patients with seizure disorders to avoid the potential CNS toxicity of the drug.167 Pyrimethamine should be administered with leucovorin when being used for the treatment of toxoplasmosis.134,167 If signs of folic or folinic acid deficiency occur during pyrimethamine therapy, dosage of the drug should be reduced or the drug discontinued, depending on the response of the patient.167 Leucovorin should be administered orally, IM, or IV in a dosage of 5-15 mg daily until normal hematopoiesis is restored.167

If pyrimethamine is administered to patients with seizure disorders for the treatment of toxoplasmosis, therapy should be initiated with a small dose to avoid the potential CNS toxicity of the drug.167

Patients receiving pyrimethamine should be warned to discontinue the drug and seek medical attention immediately at the first appearance of rash, sore throat, fever, arthralgia, cough, shortness of breath, pallor, purpura, jaundice, or glossitis.167

Pyrimethamine should be used with caution in patients with impaired renal or hepatic function.167

Pediatric Precautions

Patients should be warned to keep pyrimethamine out of the reach of children.167 Children are extremely susceptible to adverse effects from an overdosage of pyrimethamine and accidental ingestion of pyrimethamine has been fatal in children.167

Geriatric Precautions

Clinical studies of pyrimethamine did not include sufficient numbers of patients 65 years of age and older to determine whether geriatric patients respond differently than younger patients.167

While other clinical experience has not revealed age-related differences in response, dosage for geriatric patients should be selected cautiously, usually initiating therapy at the low end of the dosage range.167 The greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy observed in the elderly also should be considered.167

Mutagenicity and Carcinogenicity

Pyrimethamine was not mutagenic in vitro in the microbial mutagen (Ames) test system,167,168 the REC assay, or Escherichia coli WP2 assay.167 The drug, however, has caused mutagenic effects in mammalian cell systems (e.g., mouse lymphoma assay in the absence of exogenous metabolic activation, human lymphocyte).167 Analysis of bone marrow from rats that received pyrimethamine has revealed an increased number of structural and numerical chromosomal aberrations.167 Pyrimethamine has been found to be mutagenic in laboratory animals and in human bone marrow following 3 or 4 consecutive daily doses totaling 200-300 mg.168

Pyrimethamine has been reported to cause a significant increase in the number of lung tumors per mouse when high doses of the drug (25 mg/kg) were given intraperitoneally.167 There have been at least 2 reports of cancer associated with long-term use of pyrimethamine for the treatment of toxoplasmosis;167 one 51-year-old woman developed chronic granulocytic leukemia after receiving the drug for 2 years and one 56-year-old patient developed reticulum cell sarcoma after receiving the drug for 14 months.167

Pregnancy, Fertility, and Lactation

Pregnancy

Pyrimethamine has been shown to be teratogenic in rats, hamsters, and miniature pigs.167 There are no adequate and controlled studies to date in humans.167 The manufacturer states that pyrimethamine should be used during pregnancy only if potential benefits justify the potential risk to the fetus.167 If pyrimethamine is administered during pregnancy for the treatment of toxoplasmosis, concurrent administration of leucovorin is strongly recommended.167 Women of childbearing potential should be warned against becoming pregnant while receiving pyrimethamine.167

The US Centers for Disease Control and Prevention (CDC), National Institutes of Health (NIH), and HIV Medicine Association of the Infectious Diseases Society of America (IDSA) state that, although pyrimethamine has been associated with birth defects in animals, human data have not suggested an increased risk for defects and the drug can be administered to pregnant women after the first trimester.155 These experts state that recommended treatment of Toxoplasma gondii encephalitis in pregnant women, including the use of pyrimethamine, should be the same as that for nonpregnant adults.155

Pyrimethamine administered orally to rats in dosages 7 times the usual human dosage for prevention of malaria or 2.5 time the human dosage for treatment of toxoplasmosis was teratogenic and caused increases in abnormalities such as cleft palate, bradygnathia, oligodactyly, and microphthalmia.167 Pyrimethamine also caused meningocele in hamsters and cleft palate in miniature pigs when given in oral dosages 170 or 5 times the human dosage for prevention of malaria or treatment of toxoplasmosis, respectively.167

Lactation

Pyrimethamine is distributed into milk.147,167 It is estimated that approximately 3-4 mg of the drug would be ingested by a nursing infant over the first 48-hour period following administration of a single 75-mg oral dose to the mother.125

Because of the potential for serious adverse reactions from pyrimethamine in nursing infants and from concurrent use of a sulfonamide with pyrimethamine for the treatment of toxoplasmosis, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the mother.167

Folic Acid Antagonists

Because pyrimethamine and sulfonamides both interfere with folic acid synthesis in susceptible organisms, but at different stages, these drugs act synergistically against some organisms.125 This synergism has been used to therapeutic advantage in the treatment of malaria and toxoplasmosis.125

Concomitant use of pyrimethamine with other antifolate agents (e.g., sulfonamides, co-trimoxazole, trimethoprim) is not recommended since such use may increase the risk of bone marrow suppression.167 If signs of folate deficiency develop, pyrimethamine should be discontinued and leucovorin administered until normal hematopoiesis is restored.167

Myelosuppressive Agents

Concomitant use of pyrimethamine and other drugs associated with myelosuppression (e.g., methotrexate, proguanil, zidovudine) may increase the risk of bone marrow suppression.167 If signs of folate deficiency develop, pyrimethamine should be discontinued and leucovorin administered until normal hematopoiesis is restored.167

Dapsone

Because the drugs have similar adverse hematologic effects, concomitant use of pyrimethamine and dapsone may increase the risk of these adverse effects.180 Agranulocytosis has developed during the second and third months of therapy in patients receiving concomitant treatment with once-weekly pyrimethamine and dapsone.180 If pyrimethamine is used concomitantly with dapsone, the patient should be monitored more frequently than usual for adverse hematologic effects.180

Concomitant use of dapsone does not have a clinically important effect on the pharmacokinetics of pyrimethamine.125

Lorazepam

Although the clinical importance is unclear, mild hepatotoxicity has been reported in some patients receiving pyrimethamine and lorazepam concomitantly.167

Phenytoin

Because of antifolate effects, pyrimethamine and phenytoin should be used concomitantly with caution.167

Acute Toxicity

Manifestations

Overdosage of pyrimethamine may result in acute intoxication manifested by adverse GI effects (e.g., abdominal pain, nausea, severe and repeated vomiting, hematemesis) and/or CNS effects (including seizures).167 CNS toxicity may be manifested by initial excitability and generalized, prolonged seizures and followed by respiratory depression and circulatory collapse; death may occur within a few hours.167 Neurologic symptoms appear rapidly (0.5-2 hours) after acute overdosage of pyrimethamine, which suggests that overdosage of the drug causes a direct toxic effect on the CNS.167

The lowest fatal single dose of pyrimethamine reported has been 375 mg; however, there have been several children who have recovered after ingesting 375-625 mg of the drug.167

Treatment

There is no specific antidote for acute overdosage of pyrimethamine and symptomatic and supportive measures should be employed.167 Gastric lavage is recommended and may be beneficial if initiated very soon after overdosage.167

Parenteral diazepam or a barbiturate should be used to control seizures.167 Leucovorin should be administered within 2 hours of drug ingestion to be most effective in reversing the effects of pyrimethamine on the hematopoietic system.167 Because of the long half-life of pyrimethamine, peripheral blood cell counts should be performed daily for up to several weeks until the counts return to normal.167

Mechanism of Action

Pyrimethamine is a folic acid antagonist.125,167 By binding to and inhibiting dihydrofolate reductase,168 pyrimethamine inhibits the reduction of dihydrofolic acid to tetrahydrofolic acid (folinic acid) and indirectly blocks synthesis of nucleic acids in susceptible organisms.161,167

Spectrum

Pyrimethamine is a blood schizonticidal agent and is active against the asexual erythrocytic forms of susceptible Plasmodium falciparum , P. malariae , P. ovale , and P. vivax ;125,161,167 however, pyrimethamine is less effective than 4-aminoquinoline antimalarials (e.g., chloroquine) against the erythrocytic schizonts.167 Pyrimethamine usually is not gametocytocidal, but arrests sporogony in mosquitoes.125,167

Pyrimethamine also is active against Toxoplasma gondii .125 Concomitant use of pyrimethamine and sulfadiazine results in synergistic activity against T. gondii .125 There also is evidence that atovaquone or azithromycin may potentiate the antitoxoplasma activity of pyrimethamine.125

Resistance

Resistance to pyrimethamine can be readily induced in plasmodia and occurs frequently in areas where pyrimethamine has been widely used.125,161 Resistance to pyrimethamine has been reported in Plasmodium falciparum , P. vivax , and P. malariae .125

Pharmacokinetics

Absorption

Pyrimethamine is well absorbed from the GI tract.125,167

Following oral administration, peak serum concentrations of pyrimethamine reportedly occur within 2-6 hours of administration.125,167

Serum concentrations of pyrimethamine in children receiving recommended dosages are similar to those in adults.125

Distribution

Pyrimethamine is distributed mainly to the kidneys, lungs, liver, and spleen.106,125 The drug also is distributed into CSF in concentrations that are 10-27% of those reported in serum.125

Pyrimethamine is approximately 80-90% bound to plasma proteins.161,167

Pyrimethamine crosses the placenta168 and is distributed into milk.147,167 Following oral administration of a single 50- or 70-mg dose of pyrimethamine, concentrations of the drug in milk reportedly range from 3.1-3.3 mcg/mL at 6 hours after the dose and are still detectable in milk up to 48 hours after the dose.125

Elimination

Pyrimethamine has a plasma half-life of approximately 96 hours.167

Pyrimethamine is metabolized in the liver125 to several unidentified metabolites.168 Unchanged drug and metabolites are eliminated principally by the kidneys.125,168

Half-life of pyrimethamine may not be affected by end-stage renal failure.125

Chemistry and Stability

Chemistry

Pyrimethamine, a diaminopyrimidine, is a folic acid antagonist.125,161,167 Pyrimethamine is commercially available in the US only as a single-entity preparation.167 A fixed-combination preparation containing sulfadoxine, a long-acting sulfonamide, and pyrimethamine (sulfadoxine/pyrimethamine; Fansidar^®) was previously available in the US168 and may still be available in other countries.161

Pyrimethamine occurs as a white, crystalline powder and is practically insoluble in water and slightly soluble in alcohol.

Stability

Pyrimethamine tablets should be stored at 15-25°C in tight, light-resistant containers.108,167

Pyrimethamine tablets have been crushed to prepare oral suspensions of the drug in water, cherry syrup, or sucrose-containing solutions.109 Aqueous suspensions of pyrimethamine are relatively stable at room temperature, but sugar appears to adversely affect stability of the drug.109 If cherry syrup or sucrose-containing solutions are used as vehicles, the oral suspension should be stored at room temperature and used within 5-7 days.109

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