Pyrimethamine (Monograph)

Brand name: Daraprim
Drug class: Antimalarials
VA class: AP101
CAS number: 58-14-0

Medically reviewed by Drugs.com on Feb 26, 2024. Written by ASHP.

Introduction

Antimalarial and antiprotozoal agent; folic acid antagonist.^{125 161 167}

Uses for Pyrimethamine

Cystoisosporiasis

Pyrimethamine (and leucovorin) used alone for treatment of cystoisosporiasis caused by Cystoisospora belli^{† [off-label]} (formerly Isospora belli) when drug of choice (co-trimoxazole) cannot be used.^{134 155 156 192} Recommended by CDC, NIH, IDSA, and AAP as preferred alternative for 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}

Pyrimethamine (and leucovorin) used alone for chronic maintenance therapy (secondary prophylaxis) of cystoisosporiasis^{† [off-label]} in HIV-infected adults, adolescents, and children when drug of choice (co-trimoxazole) cannot be used.^{155 156} Recommended by CDC, NIH, IDSA, and AAP as preferred alternative in those who cannot tolerate co-trimoxazole.^{155 156}

Malaria

Pyrimethamine has been used in the past for prevention (prophylaxis) of malaria caused by susceptible Plasmodium.¹⁶⁷ Pyrimethamine-resistant strains prevalent worldwide;¹⁶⁷ no longer suitable for prevention of malaria in most areas¹⁶⁷ and not included in CDC recommendations for prevention of malaria.¹¹⁵

Pyrimethamine has been used in the past for treatment of acute uncomplicated malaria.¹⁶⁷ Pyrimethamine-resistant strains prevalent worldwide;¹⁶⁷ cannot be used alone for treatment of malaria^{161 167} and not included in CDC recommendations for treatment of malaria.¹⁴³

Fixed-combination preparation containing sulfadoxine and pyrimethamine (sulfadoxine/pyrimethamine; Fansidar) has been used for prevention of malaria and treatment of acute uncomplicated malaria caused by chloroquine-resistant P. falciparum.^{128 139 168 188 189} 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} severe and sometimes fatal adverse reactions reported when fixed combination used for malaria prevention (see Dermatologic and Hypersensitivity Reactions under Cautions).^{111 112 113 114 132 139 144 145 168} Fixed combination no longer commercially available in US and not included in CDC recommendations for prevention or treatment of malaria.^{115 143} Fixed combination may still be used for 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 risk of malaria in specific countries and mosquito avoidance measures and recommendations regarding whether prevention of malaria is indicated and choice of antimalarials for prevention are available from CDC at [Web] and [Web].¹¹⁵

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

Pneumocystis jiroveci Pneumonia

Pyrimethamine (and leucovorin) used in conjunction with dapsone for prevention of initial episodes (primary prophylaxis) of Pneumocystis jiroveci (formerly Pneumocystis carinii) pneumonia^{† [off-label]} (PCP) in HIV-infected adults and adolescents.^{134 155 171 173 174 175 176 177 178 179}

Pyrimethamine (and leucovorin) used in conjunction with dapsone for chronic maintenance therapy to prevent recurrence (secondary prophylaxis) of PCP^{† [off-label]} in HIV-infected adults and adolescents.^{134 155}

Co-trimoxazole generally drug of choice for primary and secondary prophylaxis of PCP in HIV-infected adults, adolescents, and children.^{134 155 156}

If co-trimoxazole cannot be used (e.g., because of intolerance), alternative regimens recommended by CDC, NIH, IDSA, and others for primary or secondary prophylaxis of PCP in HIV-infected adults and adolescents are dapsone, dapsone in conjunction with pyrimethamine (and leucovorin), aerosolized pentamidine, or atovaquone (with or without pyrimethamine and leucovorin).^{134 155}

Pyrimethamine regimens not included in CDC, NIH, IDSA, and AAP recommendations for primary or secondary prophylaxis of PCP in HIV-infected children.¹⁵⁶

Toxoplasmosis

Pyrimethamine (and leucovorin) used in conjunction with sulfadiazine, clindamycin, atovaquone, or azithromycin for treatment of toxoplasmosis caused by Toxoplasma gondii.^{134 155 156 167}

CDC, NIH, IDSA, and others recommend pyrimethamine (and leucovorin) used in conjunction with sulfadiazine as the regimen of choice for initial treatment of toxoplasmosis, including toxoplasmosis in HIV-infected adults, adolescents, and children.^{134 155 156}

Pyrimethamine (and leucovorin) used in conjunction with clindamycin is the preferred alternative for treatment of toxoplasmosis in HIV-infected adults, adolescents, and children unable to tolerate sulfadiazine or who fail to respond to or relapse after treatment with regimen of choice.^{134 155 156} Other alternatives 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 these regimens not studied in children.¹⁵⁶

Pyrimethamine (and leucovorin) used in conjunction with sulfadiazine is the regimen of choice for treatment of congenital toxoplasmosis.¹⁵⁶ Empiric treatment of congenital toxoplasmosis should be strongly considered if the mother had symptomatic or asymptomatic Toxoplasma infection during pregnancy, even if the mother received toxoplasmosis treatment during the pregnancy.¹⁵⁶

Pyrimethamine (and leucovorin) used in conjunction with dapsone is the recommended alternative for prevention of T. gondii encephalitis (primary prophylaxis)^{† [off-label]} in HIV-infected adults, adolescents, and children ≥1 month of age when the regimen of choice (co-trimoxazole) cannot be used.^{155 156 178 195 210 211} Pyrimethamine (and leucovorin) used in conjunction with atovaquone is another alternative for primary prophylaxis of toxoplasmosis in HIV-infected adults, adolescents, and children 4–24 months of age when the regimen of choice (co-trimoxazole) cannot be used.^{134 155 156}

Pyrimethamine (and leucovorin) used in conjunction with sulfadiazine is the regimen of choice for chronic maintenance therapy (secondary prophylaxis) to prevent relapse of T. gondii encephalitis^† in HIV-infected adults, adolescents, and children who have completed treatment for the disease.^{155 156}

Pyrimethamine (and leucovorin) used in conjunction with clindamycin is an alternative for secondary prophylaxis in HIV-infected adults, adolescents, and children when the regimen of choice cannot be used;^{155 156} pyrimethamine (and leucovorin) used in conjunction with atovaquone is another alternative in HIV-infected adults and adolescents.¹⁵⁵

Pyrimethamine Dosage and Administration

Administration

Oral Administration

Administer orally.¹⁶⁷ If anorexia or vomiting occurs, give with a meal to minimize adverse GI effects.¹⁶⁷

For children and others unable to swallow tablets, extemporaneous oral suspensions of pyrimethamine may be prepared by crushing pyrimethamine tablets (single-entity preparation) and mixing with water, cherry syrup, or other sucrose-containing solution.¹⁰⁹ (See Stability.) Shake oral suspension prior to each dose.¹⁰⁹

Dosage

Pediatric Patients

Cystoisosporiasis†

Treatment in HIV-infected Children†

Oral

1 mg/kg once daily with oral leucovorin (10–25 mg once daily) for 14 days.¹⁵⁶

Treatment in HIV-infected Adolescents†

Oral

50–75 mg once daily with oral leucovorin (10–25 mg once daily).¹⁵⁵

Prevention of Recurrence (Secondary Prophylaxis) in HIV-infected Children†

Oral

1 mg/kg (up to 25 mg) once daily with oral leucovorin (10–25 mg once daily).¹⁵⁶

Can consider discontinuing secondary prophylaxis against cystoisosporiasis if there is sustained improvement for >6 months in CD4⁺ T-cell counts or CD4 percentages (change from CDC immunologic category 3 to category 1 or 2).¹⁵⁶

Prevention of Recurrence (Secondary Prophylaxis) in HIV-infected Adolescents†

Oral

25 mg once daily with oral leucovorin (5–10 mg once daily).¹⁵⁵

Can consider discontinuing secondary prophylaxis of cystoisosporiasis if CD4⁺ T-cell counts remain >200 cells/mm³ for >6 months in response to antiretroviral therapy and there is no evidence of active C. belli infection.¹⁵⁵

Malaria

Prevention of Malaria

Oral

Infants and children <4 years of age: Manufacturer recommends 6.25 mg once weekly.¹⁶⁷

Children 4–10 years of age: Manufacturer recommends 12.5 mg once weekly.¹⁶⁷

Children >10 years of age: Manufacturer recommends 25 mg once weekly.¹⁶⁷

Pyrimethamine-resistant strains prevalent worldwide; not suitable for prevention of malaria in most areas.¹⁶⁷ (See Malaria under Uses.)

Treatment of Acute Malaria

Oral

Children 4–10 years of age: Manufacturer recommends 25 mg once daily for 2 days, followed by 12.5 mg once weekly for ≥10 weeks.¹⁶⁷

Pyrimethamine-resistant strains prevalent worldwide; do not use alone for treatment of acute malaria.¹⁶⁷ (See Malaria under Uses.)

Pneumocystis jiroveci (Pneumocystis carinii) Pneumonia†

Prevention (Primary Prophylaxis) in HIV-infected Adolescents†

Oral

50 mg once weekly with oral leucovorin (25 mg once weekly) and oral dapsone (50 mg once daily).^{134 155} Alternatively, 75 mg once weekly with oral leucovorin (25 mg once weekly) and oral dapsone (200 mg once weekly).^{134 155}

Alternatively, 25 mg once daily with oral leucovorin (10 mg once daily) and oral atovaquone (1.5 g once daily).¹⁵⁵

Criteria for initiating or discontinuing primary prophylaxis of PCP^† in HIV-infected adolescents are the same as those for adults.¹⁵⁵ (See Adults under Dosage and Administration.)

Prevention of Recurrence (Secondary Prophylaxis) in HIV-infected Adolescents†

Oral

50 mg once weekly with oral leucovorin (25 mg once weekly) and oral dapsone (50 mg once daily).^{134 155} Alternatively, 75 mg once weekly with oral leucovorin (25 mg once weekly) and oral dapsone (200 mg once weekly).^{134 155}

Alternatively, 25 mg once daily with oral leucovorin (10 mg once daily) and oral atovaquone (1.5 g once daily).¹⁵⁵

Criteria for initiating or discontinuing secondary prophylaxis of PCP in adolescents are the same as those for adults.¹⁵⁵ (See Adults under Dosage and Administration.)

Toxoplasmosis

Treatment

Oral

Manufacturer recommends 1 mg/kg daily in 2 divided doses for 2–4 days, then reduce dosage by 50% and continue for approximately 1 month.¹⁶⁷ Must be used in conjunction with a sulfonamide.¹⁶⁷

Treatment of Congenital Toxoplasmosis

Oral

2 mg/kg once daily for 2 days, then 1 mg/kg once daily for 2–6 months, then 1 mg/kg 3 times weekly; used with oral or IM leucovorin (10 mg with each pyrimethamine dose) and oral sulfadiazine (50 mg/kg twice daily).¹⁵⁶

Recommended duration in HIV-infected infants is 12 months.¹⁵⁶

Treatment in HIV-infected Infants and Children

Oral

2 mg/kg (up to 50 mg) once daily for 3 days, then 1 mg/kg (up to 25 mg) once daily; used 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, pyrimethamine 2 mg/kg (up to 50 mg) once daily for 3 days, then 1 mg/kg (up to 25 mg) once daily; used with oral leucovorin (10–25 mg once daily) and oral or IV clindamycin (5–7.5 mg/kg [up to 600 mg] 4 times daily).¹⁵⁶

Continue acute treatment for ≥6 weeks; longer duration may be appropriate if disease is extensive or response incomplete at 6 weeks.¹⁵⁶

Treatment in HIV-infected Adolescents

Oral

200-mg loading dose, then 50 mg once daily in those weighing <60 kg or 75 mg once daily in those weighing ≥60 kg; used 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 <60 kg or 1.5 g every 6 hours in those weighing ≥60 kg).¹⁵⁵

Alternatively, 200-mg loading dose, then 50 mg once daily in those weighing <60 kg or 75 mg once daily in those weighing ≥60 kg; used with oral leucovorin (10–25 mg once daily; may be increased to 50 mg once or twice daily) and 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

Continue acute treatment for ≥6 weeks; longer duration may be appropriate if disease is extensive or response incomplete at 6 weeks.¹⁵⁵

Prevention (Primary Prophylaxis) in HIV-Infected Infants and Children†

Oral

1 mg/kg (up to 25 mg) once daily used with oral leucovorin (5 mg once every 3 days) and oral dapsone (2 mg/kg or 15 mg/m² once daily [up to 25 mg]) in those ≥1 month of age.¹⁵⁶

If pyrimethamine (and leucovorin) used in conjunction with atovaquone as alternative for primary prophylaxis in those 4–24 months of age, regimen of pyrimethamine 1 mg/kg or 15 mg/m² (up to 25 mg) once daily with oral leucovorin (5 mg once every 3 days) and oral atovaquone (45 mg/kg once daily) recommended.¹⁵⁶

Initiate primary prophylaxis against T. gondii encephalitis in all HIV-infected children <6 years of age with severe immunosuppression who are seropositive for Toxoplasma IgG antibody and have CD4⁺ T-cell percentages <15%.¹⁵⁶ Initiate primary prophylaxis in HIV-infected children >6 years of age who are seropositive for Toxoplasma IgG antibody with CD4⁺ T-cell counts <100/mm³.¹⁵⁶

Safety of discontinuing primary prophylaxis against toxoplasmosis in HIV-infected children whose immunologic status improves with potent antiretroviral therapy not extensively studied to date.¹⁵⁶ Do not discontinue primary prophylaxis in HIV-infected children <1 year of age.¹⁵⁶ Based on data from adults, can consider discontinuing primary prophylaxis in those 1 to <6 years of age who have received ≥6 months of antiretroviral therapy if CD4⁺ T-cell percentages remain ≥15% for >3 months.¹⁵⁶ For children ≥6 years of age who have received ≥6 months of antiretroviral therapy, can consider discontinuing if CD4⁺ T-cell counts remain >200/mm³ for >3 months.¹⁵⁶

Reinitiate primary prophylaxis against toxoplasmosis if CD4⁺ T-cell percentages decrease to <15% in HIV-infected children <6 years of age or if CD4⁺ T-cell counts decrease to <100–200/mm³ in HIV-infected children ≥6 years of age.¹⁵⁶

Prevention (Primary Prophylaxis) in HIV-Infected Adolescents†

Oral

50 mg once weekly used with oral leucovorin (25 mg once weekly) and oral dapsone (50 mg once daily).¹⁵⁵ Alternatively, 75 mg once weekly used with oral leucovorin (25 mg once weekly) and oral dapsone (200 mg once weekly).¹⁵⁵

Alternatively, 25 mg once daily used with oral leucovorin (10 mg once daily) and oral atovaquone (1.5 g once daily).¹⁵⁵

Criteria for initiating or discontinuing primary prophylaxis against toxoplasmosis in adolescents are the same as those for adults.¹⁵⁵ (See Adults under Dosage and Administration.)

Prevention of Recurrence (Secondary Prophylaxis) in HIV-infected Infants and Children†

Oral

1 mg/kg or 15 mg/m² (up to 25 mg) once daily used with oral leucovorin (5 mg once every 3 days) and oral sulfadiazine (42.5–60 mg/kg twice daily [up to 2–4 g daily]) or, alternatively, oral clindamycin (7–10 mg/kg 3 times daily).¹⁵⁶

If pyrimethamine (and leucovorin) used in conjunction with atovaquone as alternative for secondary prophylaxis in those 4–24 months of age, regimen of pyrimethamine 1 mg/kg or 15 mg/m² (up to 25 mg) once daily with oral leucovorin (5 mg once every 3 days) and oral atovaquone (45 mg/kg once daily) recommended.¹⁵⁶

Safety of discontinuing secondary prophylaxis against toxoplasmosis in HIV-infected children receiving potent antiretroviral therapy not extensively studied.¹⁵⁶ If child has completed initial toxoplasmosis treatment, is asymptomatic for toxoplasmosis, and has received ≥6 months of antiretroviral therapy, can consider discontinuing secondary prophylaxis in those 1 to <6 years of age if CD4⁺ T-cell percentages remain ≥15% for >6 consecutive months or in those ≥6 years of age if CD4⁺ T-cell counts remain >200/mm³ for >6 consecutive months.¹⁵⁶

Reinitiate secondary prophylaxis against toxoplasmosis if CD4⁺ T-cell percentages decrease to <15% in HIV-infected children <6 years of age or if CD4⁺ T-cell counts decrease to <200/mm³ in HIV-infected children ≥6 years of age.¹⁵⁶

Prevention of Recurrence (Secondary Prophylaxis) in HIV-infected Adolescents†

Oral

25–50 mg once daily used with oral leucovorin (10–25 mg once daily) and oral sulfadiazine (2–4 g daily in 2–4 divided doses) or, alternatively, oral clindamycin (600 mg every 8 hours).¹⁵⁵

Alternatively, 25 mg once daily with oral leucovorin (10 mg once daily) and oral atovaquone (750–1500 mg twice daily).¹⁵⁵

Criteria for initiating or discontinuing secondary prophylaxis against toxoplasmosis in adolescents are the same as those for adults.¹⁵⁵ (See Adults under Dosage and Administration.)

Adults

Cystoisosporiasis†

Treatment in HIV-infected Adults†

Oral

50–75 mg once daily with oral leucovorin (10–25 mg once daily).¹⁵⁵

Prevention of Recurrence (Secondary Prophylaxis) in HIV-infected Adults†

Oral

25 mg once daily with oral leucovorin (5–10 mg once daily).¹⁵⁵

Can consider discontinuing secondary prophylaxis of cystoisosporiasis if CD4⁺ T-cell counts remain >200 cells/mm³ for >6 months in response to antiretroviral therapy and there is no evidence of active C. belli infection.¹⁵⁵

Malaria

Prevention of Malaria

Oral

Manufacturer recommends 25 mg once weekly.¹⁶⁷

Pyrimethamine-resistant strains prevalent worldwide; not suitable for prevention of malaria in most areas.¹⁶⁷ (See Malaria under Uses.)

Treatment of Acute Malaria

Oral

Manufacturer recommends 50 mg once daily for 2 days, followed by 25 mg once weekly for ≥10 weeks.¹⁶⁷

Manufacturer states 25 mg once daily for 2 days in conjunction with a sulfonamide will initiate transmission control and suppression of non-falciparum malaria.¹⁶⁷

Pyrimethamine-resistant strains prevalent worldwide; do not use alone for treatment of acute malaria.¹⁶⁷ (See Malaria under Uses.)

Pneumocystis jiroveci (Pneumocystis carinii) Pneumonia†

Prevention (Primary Prophylaxis)†

Oral

50 mg once weekly used with oral leucovorin (25 mg once weekly) and oral dapsone (50 mg once daily).^{134 155} Alternatively, 75 mg once weekly with oral leucovorin (25 mg once weekly) and oral dapsone (200 mg once weekly).^{134 155}

Alternatively, 25 mg once daily with oral leucovorin (10 mg once daily) and oral atovaquone (1.5 g once daily).¹⁵⁵

Initiate primary prophylaxis against PCP in HIV-infected adults and adolescents with CD4⁺ T-cell counts <200/mm³ or a history of oropharyngeal candidiasis.¹⁵⁵ Also consider primary prophylaxis if CD4⁺ T-cell percentage is <14% or there is a history of an AIDS-defining illness.¹⁵⁵

Primary prophylaxis against PCP generally can be discontinued in HIV-infected adults and adolescents if CD4⁺ T-cell counts remain ≥200/mm³ for ≥3 months in response to antiretroviral therapy.¹⁵⁵

Reinitiate primary prophylaxis if CD4⁺ T-cell count decreases to <200/mm³.¹⁵⁵

Prevention of Recurrence (Secondary Prophylaxis)†

Oral

50 mg once weekly used with oral leucovorin (25 mg once weekly) and oral dapsone (50 mg once daily).^{134 155} Alternatively, 75 mg once weekly with oral leucovorin (25 mg once weekly) and oral dapsone (200 mg once weekly).^{134 155}

Alternatively, 25 mg once daily with oral leucovorin (10 mg once daily) and oral atovaquone (1.5 g once daily).¹⁵⁵

Initiate chronic maintenance therapy (secondary prophylaxis) to prevent recurrence in those with a history of PCP.¹⁵⁵

Secondary prophylaxis against PCP generally can be discontinued in HIV-infected adults and adolescents if CD4⁺ T-cell counts remain >200/mm³ for >3 months in response to antiretroviral therapy.¹⁵⁵

Reinitiate secondary prophylaxis if CD4⁺ T-cell counts decrease to <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 >200/mm³.¹⁵⁵

Toxoplasmosis

Treatment

Oral

Manufacturer recommends 50–75 mg once daily in conjunction with a sulfonamide for 1–3 weeks; reduce dosage of both drugs by 50% and continue for 4–5 additional weeks.¹⁶⁷

Treatment in HIV-infected Adults

Oral

200-mg loading dose, then 50 mg once daily in those weighing <60 kg or 75 mg once daily in those weighing ≥60 kg; used 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 <60 kg or 1.5 g every 6 hours in those weighing ≥60 kg).¹⁵⁵

Alternatively, 200-mg loading dose, then 50 mg once daily in those weighing <60 kg or 75 mg once daily in those weighing ≥60 kg; used with oral leucovorin (10–25 mg once daily; may be increased to 50 mg once or twice daily) and 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

Continue acute treatment for ≥6 weeks; longer duration may be appropriate if disease is extensive or response incomplete at 6 weeks.¹⁵⁵

Prevention (Primary Prophylaxis) in HIV-Infected Adults†

Oral

50 mg once weekly used with oral leucovorin (25 mg once weekly) and oral dapsone (50 mg once daily).¹⁵⁵ Alternatively, 75 mg once weekly with oral leucovorin (25 mg once weekly) and oral dapsone (200 mg once weekly).¹⁵⁵

Alternatively, 25 mg once daily used with oral leucovorin (10 mg once daily) and oral atovaquone (1.5 g once daily).¹⁵⁵

Primary prophylaxis against toxoplasmosis generally can be discontinued in HIV-infected adults and adolescents if CD4⁺ T-cell counts remain >200/mm³ for >3 months in response to antiretroviral therapy.¹⁵⁵

Reinitiate primary prophylaxis if CD4⁺ T-cell counts decrease to <100–200/mm³.¹⁵⁵

Prevention of Recurrence (Secondary Prophylaxis) in HIV-infected Adults†

Oral

25–50 mg once daily used with oral leucovorin (10–25 mg once daily) and oral sulfadiazine (2–4 g daily given in 2–4 divided doses) or, alternatively, oral clindamycin (600 mg every 8 hours).¹⁵⁵

Alternatively, 25 mg once daily with oral leucovorin (10 mg once daily) and oral atovaquone (750–1500 mg twice daily).¹⁵⁵

Initiate chronic maintenance therapy (secondary prophylaxis) in all patients who have completed initial treatment of toxoplasmic encephalitis.¹⁵⁵

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 remain >200/mm³ for >6 months in response to antiretroviral therapy.¹⁵⁵ Some experts would obtain a brain magnetic resonance image as part of their evaluation to determine whether or not discontinuance of secondary prophylaxis is appropriate.¹⁵⁵

Reinitiate secondary prophylaxis if CD4⁺ T-cell counts decrease to <200/mm³.¹⁵⁵

Prescribing Limits

Pediatric Patients

Cystoisosporiasis†

Prevention of Recurrence (Secondary Prophylaxis) in HIV-infected Children†

Oral

Maximum 25 mg daily.¹⁵⁶

Toxoplasmosis

Treatment of HIV-infected Children

Oral

Maximum 25–50 mg per dose.¹⁵⁶

Prevention of Recurrence (Secondary Prophylaxis) in HIV-infected Infants and Children†

Oral

Maximum 25 mg per dose.¹⁵⁶

Special Populations

No special population dosage recommendation at this time.¹⁶⁷

Cautions for Pyrimethamine

Contraindications

• Hypersensitivity to pyrimethamine or any ingredient in the formulation.¹⁶⁷

• Megaloblastic anemia caused by folate deficiency.¹⁶⁷

Warnings/Precautions

Warnings

Hematologic Effects

High pyrimethamine dosage may cause folic acid deficiency and cause reversible bone marrow depression.^{125 167} Use with caution in patients with possible folate deficiency, including malabsorption syndrome, alcoholism, pregnancy (see Pregnancy under Cautions), and in those receiving drugs affecting folate levels (see Interactions).¹⁶⁷ Hematologic effects may also occur with lower pyrimethamine dosages in certain individuals.¹⁶⁷

Reduce dosage or discontinue if signs of folic or folinic acid deficiency occur.¹⁶⁷ Perform CBCs twice weekly.¹⁶⁷ (See Laboratory Monitoring under Cautions.)

Pyrimethamine dosage used for treatment of toxoplasmosis approaches the toxic level and is associated with adverse effects resulting from folic acid deficiency.¹⁶⁷ Megaloblastic anemia, leukopenia, thrombocytopenia, and pancytopenia reported.^{125 167} When pyrimethamine is used for treatment of toxoplasmosis, give leucovorin (folinic acid) concomitantly.^{134 167} (See Toxoplasmosis under Pediatric Patients and also under Adults, in Dosage and Administration.)

Carcinogenicity

Manufacturer states pyrimethamine may be carcinogenic.¹⁶⁷ Chronic granulocytic leukemia and reticulum cell sarcoma reported rarely after long-term use for treatment of toxoplasmosis; increase in lung tumors reported in animal study.¹⁶⁷

Sensitivity Reactions

Dermatologic and Hypersensitivity Reactions

Hypersensitivity reactions, including severe reactions such as erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, and anaphylaxis, reported with pyrimethamine, especially when used with a sulfonamide.¹⁶⁷

Severe, sometimes fatal, hypersensitivity reactions have occurred in patients receiving 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} fatal reaction involving the skin, liver, and kidneys,¹¹² and fatal hepatitis also reported.¹³² The fixed-combination preparation no longer commercially available in US,¹⁶⁸ but may still be available in other countries.¹⁶¹

Discontinue pyrimethamine at first sign of rash, sore throat, fever, arthralgia, cough, shortness of breath, pallor, jaundice, or glossitis.¹⁶⁷

General Precautions

GI Effects

Adverse GI effects (anorexia, abdominal cramps, vomiting, atrophic glossitis, gastritis)¹⁶⁷ may occur with high pyrimethamine dosage.¹⁶⁷ Administration with a meal may reduce anorexia and vomiting.¹⁶⁷

Nervous System Effects

Ataxia, tremors, and seizures reported with high pyrimethamine dosage.¹²⁵ Headache, light-headedness, insomnia, depression, malaise, fatigue, and irritability also reported rarely.¹²⁵

In patients with seizure disorders being treated for toxoplasmosis, use low initial pyrimethamine dosage to avoid potential nervous system toxicity.¹⁶⁷

Laboratory Monitoring

Monitor CBC, including platelet counts, twice weekly in patients receiving high pyrimethamine dosage.¹⁶⁷

Specific Populations

Pregnancy

Category C.¹⁶⁷

Manufacturer states use during pregnancy only when potential benefits outweigh possible risks;¹⁶⁷ if pyrimethamine is used to treat toxoplasmosis during pregnancy, administer leucovorin concurrently to decrease hematologic toxicity.¹⁶⁷

CDC, NIH, and 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 first trimester.¹⁵⁵ These experts state that recommended treatment of T. gondii encephalitis in pregnant women, including use of pyrimethamine, should be the same as that for nonpregnant adults.¹⁵⁵

Warn women of childbearing potential to avoid becoming pregnant while receiving the drug.¹⁶⁷

Lactation

Pyrimethamine distributed into milk.^{147 167} Discontinue nursing or the drug, taking into account the importance of the drug to the woman.¹⁶⁷

Pediatric Use

Infants and children are extremely susceptible to adverse effects from pyrimethamine overdosage;¹⁶⁷ fatalities reported after accidental ingestion.¹⁶⁷

Keep out of the reach of children.¹⁶⁷

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine if they respond differently than younger adults; clinical experience has not identified differences.¹⁶⁷

Select dosage with caution because of possible age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.¹⁶⁷

Common Adverse Effects

Hypersensitivity reactions, GI effects, myelosuppression.¹⁶⁷

Drug Interactions

Specific Drugs

Pyrimethamine Pharmacokinetics

Absorption

Bioavailability

Well absorbed from GI tract;^{125 167} peak serum concentrations attained within 2–6 hours.^{125 167}

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

Distribution

Extent

Distributed mainly to kidneys, lungs, liver, and spleen.^{106 125}

Distributed into CSF.¹²⁵

Crosses the placenta.¹⁶⁸

Distributed into milk.^{147 167}

Plasma Protein Binding

Approximately 80–90%.^{161 167}

Elimination

Metabolism

Metabolized in the liver¹²⁵ to several unidentified metabolites.¹⁶⁸

Elimination Route

Unchanged drug and metabolites eliminated principally by kidneys.^{125 168}

Half-life

Approximately 96 hours.¹⁶⁷

Special Populations

Half-life may not be affected by end-stage renal failure.^{125 168}

Stability

Storage

Oral

Tablets

15–25°C in tight, light resistant container.^{108 167}

Extemporaneously Prepared Suspension

Aqueous suspension prepared using commercially available pyrimethamine tablets and water, cherry syrup, or other sucrose-containing solution: Room temperature; use within 5–7 days.¹⁰⁹

Actions

• Inhibits folic acid synthesis by inhibiting dihydrofolate reductase.^{125 161} Because reduction of dihydrofolic acid to tetrahydrofolic acid (folinic acid) is inhibited, the drug indirectly blocks synthesis of nucleic acids in susceptible organisms.^{161 167}

• Blood schizonticidal agent active against asexual erythrocytic forms of susceptible P. falciparum, P. malariae, P. ovale, and P. vivax.^{125 161}

• Active against T. gondii.¹²⁵ Concomitant use of pyrimethamine and sulfadiazine results in synergistic activity against T. gondii;¹²⁵ concomitant use with atovaquone or azithromycin also potentiates antitoxoplasma activity of pyrimethamine.¹²⁵

• Pyrimethamine resistance may be induced in plasmodia and frequently occurs in areas where the drug has been widely used.^{125 161} Pyrimethamine resistance reported in P. falciparum, P. malariae, and P. vivax.¹²⁵

Advice to Patients

• Advise patients to take pyrimethamine with meals if anorexia or vomiting occurs.¹⁶⁷

• Advise patients not to exceed recommended dosage.¹⁶⁷

• Advise patients to discontinue pyrimethamine and inform clinicians at the first appearance of rash, sore throat, fever, arthralgia, cough, shortness of breath, pallor, purpura, jaundice, or glossitis.¹⁶⁷

• Importance of keeping pyrimethamine out of the reach of children.¹⁶⁷

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.¹⁶⁷

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.¹⁶⁷ (See Pregnancy under Cautions.)

• Importance of informing patients of other important precautionary information.¹⁶⁷ (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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