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Pyrimethamine, Sulfadoxine and Pyrimethamine

Class: Antimalarials
VA Class: AP101
CAS Number: 58-14-0
Brands: Daraprim

Introduction

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

Uses for Pyrimethamine, Sulfadoxine and Pyrimethamine

Cystoisosporiasis

Pyrimethamine (and leucovorin) used alone for treatment of cystoisosporiasis caused by Cystoisospora belli (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 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 malaria161 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

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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 and .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 (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 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) 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, Sulfadoxine and 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, Sulfadoxine and 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

Interactions for Pyrimethamine, Sulfadoxine and Pyrimethamine

Specific Drugs

Drug

Interaction

Comments

Dapsone

Additive adverse hematologic effects; increased risk of agranulocytosis180

No clinically important effect on pyrimethamine pharmacokinetics125

Monitor for adverse hematologic effects more frequently than usual180

Folic acid antagonists (e.g., sulfonamides, co-trimoxazole, trimethoprim)

Pyrimethamine and sulfonamides interfere with folic acid synthesis in susceptible organisms; possible synergism between the drugs used to therapeutic advantage in treatment of toxoplasmosis125 168 and has been used to therapeutic advantage in prevention or treatment of malaria134 167 168 188 189

Increased risk of bone marrow suppression if used with other folic acid antagonists167

Pyrimethamine used in conjunction with sulfadiazine for treatment of toxoplasmosis134 155 156 184 185

Pyrimethamine has been used in conjunction with sulfadoxine for prevention or treatment of malaria, but no longer recommended for such use143

If signs of folate deficiency develop, discontinue pyrimethamine and administer leucovorin until normal hematopoiesis restored167

Lorazepam

Mild hepatotoxicity reported when pyrimethamine and lorazepam used concomitantly167

Methotrexate

May increase risk of bone marrow suppression167

Use with caution167

Discontinue pyrimethamine if signs of folate deficiency develop;167 administer leucovorin until normal hematopoiesis restored167

Phenytoin

Decreased folic acid levels167

Use with caution167

Proguanil

May increase risk of bone marrow suppression167

Discontinue pyrimethamine if signs of folate deficiency develop;167 administer leucovorin until normal hematopoiesis restored167

Zidovudine

May increase risk of bone marrow suppression167

Discontinue pyrimethamine if signs of folate deficiency develop;167 administer leucovorin until normal hematopoiesis restored167

Pyrimethamine, Sulfadoxine and 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.

Pyrimethamine

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

25 mg

Daraprim (scored)

Amedra

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions March 5, 2014. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

Only references cited for selected revisions after 1984 are available electronically.

44. Stahel E, Degrémont A, Lagler U. Pyrimethamine/sulfadoxine resistant falciparum malaria acquired at Dar es Salaam, Tanzania. Lancet. 1982; 1:1118-9. [IDIS 150059] [PubMed 6122905]

45. Timmermanns PM, Hess U, Jones ME. Pyrimethamine/sulfadoxine resistant falciparum malaria in East Africa. Lancet. 1982; 1:1181. [IDIS 150443] [PubMed 6122952]

106. White NJ. Clinical pharmacokinetics of antimalarial drugs. Clin Pharmacokinet. 1985; 10:187-215. [IDIS 202191] [PubMed 3893840]

108. The United States pharmacopeia, 21st rev., and The national formulary, 16th ed. Rockville, MD: The United States Pharmacopeial Convention, Inc; 1985:921,990-1.

109. Collins GE (Burroughs Wellcome Co, Research Triangle Park, NC): Personal communication; 1985 Jun 25.

110. Anon. Boxed warning added to Fansidar labeling. FDA Drug Bull. 1985; 15:21.

111. Svanbom M, Rombo L, Gustafsson L. Unusual pulmonary reaction during short term prophylaxis with pyrimethamine-sulfadoxine (Fansidar). BMJ. 1984; 288:1876. [IDIS 187377] [PubMed 6428585]

112. Selby CD, Ladusans EJ, Smith PG. Fatal multisystemic toxicity associated with prophylaxis with pyrimethamine and sulfadoxine (Fansidar). BMJ. 1985; 290:113-4. [IDIS 195296] [PubMed 3155635]

113. Koch-Weser J, Hodel C, Leimer R et al. Adverse reactions to pyrimethamine/sulfadoxine. Lancet. 1982; 2:1459. [IDIS 162358] [PubMed 6129527]

114. Olsen VV, Loft S, Christensen KD. Serious reactions during malaria prophylaxis with pyrimethamine-sulfadoxine. Lancet. 1982; 2:994. [IDIS 159786] [PubMed 6127497]

115. Centers for Disease Control and Prevention. CDC health information for international travel, 2014. Atlanta, GA: US Department of Health and Human Services. Updates may be available at CDC website.

123. Montoya JG, Remington JS. Toxoplasma gondii. In: Mandell GL, Bennett JE, and Dolin R eds. Mandell, Douglas, and Bennett’s principles and practice of infectious diseases. 5th ed. New York: Churchill Livingstone; 2000:2858-88.

125. Kucers A, Crowe S, Grayson ML et al, eds. The use of antibiotics. A clinical review of antibacterial, antifungal, and antiviral drugs. 5th ed. Jordan Hill, Oxford: Butterworth-Heinemann; 1997: 905-21.

126. Herzog C, Kibbler CC, Ellis CJ et al. Falciparum malaria resistant to chloroquine and fansidar: implications for prophylaxis. BMJ. 1983; 287:947-8. [IDIS 176428] [PubMed 6412900]

127. Miller KD, Lobel HO, Pappaioanou M et al. Failures of combined chloroquine and Fansidar prophylaxis in American travelers to east Africa. J Infect Dis. 1986; 154:689-91. [IDIS 222467] [PubMed 3528321]

128. Pearson RD, Hewlett EL. Use of pyrimethamine-sulfadoxine (Fansidar) in prophylaxis against chloroquine-resistant Plasmodium falciparum and Pneumocystis carinii. Ann Intern Med. 1987; 106:714-8. [IDIS 229433] [PubMed 3551713]

132. Zitelli BJ, Alexander J, Taylor S et al. Fatal hepatic necrosis due to pyrimethamine-sulfadoxine (Fansidar). Ann Intern Med. 1987; 106:393-5. [IDIS 226755] [PubMed 2949680]

134. Anon. Drugs for parasitic infections. Treat Guidel Med Lett. 2010; 8:e1-16.

136. Fischl MA, Dickinson GM. Fansidar prophylaxis of pneumocystis pneumonia in the acquired immunodeficiency syndrome. Ann Intern Med. 1986; 105:629. [IDIS 221753] [PubMed 3489429]

138. McCormack D, Morgan WK. Fansidar hypersensitivity pneumonitis. Br J Dis Chest. 1987; 81:194-6. [PubMed 3651313]

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140. Hellgren U, Rombo L, Berg B. Adverse reactions to sulphadoxine-pyrimethamine in Swedish travelers: implications for prophylaxis. BMJ. 1987; 295:365-6. [IDIS 233139] [PubMed 2958104]

141. Lazar HP, Murphy RL, Phair JP. Fansidar and hepatic granulomas. Ann Intern Med. 1985; 102:722. [PubMed 3985527]

142. Wejstal R, Lindberg J, Malmvall BE et al. Liver damage associated with Fansidar. Lancet. 1986; 1:854-5. [IDIS 214372] [PubMed 2870335]

143. Centers for Disease Control and Prevention. CDC treatment guidelines: Treatment of malaria (guidelines for clinicians). 2013 Jul. From the CDC website. Accessed 2013 Sep 27.

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145. Miller KD, Lobel HO, Satriale RF et al. Severe cutaneous reactions among American travelers using pyrimethamine-sulfadoxine (Fansidar) for malaria prophylaxis. Am J Trop Med Hyg. 1986; 35:451-8. [PubMed 2939735]

147. Edstein MD, Veenendaal JR, Newman K et al. Excretion of chloroquine, dapsone and pyrimethamine in human milk. Br J Clin Pharmacol. 1986; 22:733-5. [IDIS 224280] [PubMed 3567020]

152. Rolston KVI, Hoy J. Role of clindamycin in the treatment of central nervous system toxoplasmosis. Am J Med. 1987; 83:551-4. [IDIS 234168] [PubMed 3661590]

153. Kaplan LD, Wofsy CB, Volberding PA et al. Treatment of patients with acquired immunodeficiency syndrome and associated manifestations. JAMA. 1987; 257:1367-74. [IDIS 226462] [PubMed 3546745]

154. Podzamczer D, Gudiol F. Clindamycin in cerebral toxoplasmosis. Am J Med. 1988; 84:800. [IDIS 241429] [PubMed 3400676]

155. Panel on Opportunistic Infections in HIV-infected Adults and Adolescents. Guidelines for prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from the Centers for Disease Control and Prevention, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America (May 7, 2013). Updates may be available at HHS AIDS Information (AIDSinfo) website.

156. Panel on Opportunistic Infection in HIV-exposed and HIV-infected children, US Department of Health and Human Services (HHS). Guidelines for the prevention and treatment of opportunistic infections in HIV-exposed and HIV-infected children: recommendations from the National Institutes of Health, Centers for Disease Control and Prevention, the HIV Medicine Association of the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the American Academy of Pediatrics (Nov 6, 2013). Updates may be available at HHS AIDS Information (AIDSinfo) website.

158. Snider WD, Simpson DM, Nielsen S et al. Neurological complications of acquired immune deficiency syndrome: analysis of 50 patients. Ann Neurol. 1983; 14:403-18. [PubMed 6314874]

159. Centers for Disease Control. Fansidar-associated fatal reaction in an HIV-infected man. MMWR Morb Mortal Wkly Rep. 1988; 37:571,572,577. [PubMed 3137443]

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161. World Health Organization (WHO). Guidelines for the treatment of malaria. 2nd edition. Geneva, Switzerland: World Health Organization; 2010. Updates may be available at WHO website.

164. Leport C, Bastuji-Garin S, Perronne C et al. An open study of the pyrimethamine-clindamycin combination in AIDS patients with brain toxoplasmosis. J Infect Dis. 1989; 160:557-8. [IDIS 305062] [PubMed 2760509]

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168. Genentech, Inc. Fansidar (sulfadoxine and pyrimethamine) tablets prescribing information. South San Francisco, CA; 2012 Aug.

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173. Clotet B, Sirera G, Romeu J et al. Twice weekly dapsone-pyrimethamine for preventing P. carinii pneumonia relapses in HIV infected patients. Int Conf AIDS. 1990; 6:225.

174. Clotet B, Sirera G, Romeu J et al. Twice weekly dapsone-pyrimethamine for preventing primary and secondary Pneumocystis carinii pneumonia (PCP): its role in the prevention of cerebral toxoplasmosis. Int Conf AIDS. 1991; 7:228.

175. Lavelle J, Falloon J, Morgan A et al. Weekly dapsone/pyrimethamine for PCP prophylaxis. Int Conf AIDS. 1991; 7:233.

176. Girard PM, Landman R, Gaudebout C et al. Dapsone-pyrimethamine (D/P) vs aerosolized pentamidine (AP) for primary prophylaxis of pneumocystis (PCP) and neurotoxoplasmosis: the PRIO group. Int Conf AIDS. 1992; 8:We48.

177. Antinori A, Murri R, Ammassari A et al. Primary prevention of Pneumocystis carinii pneumonia: an open controlled study on three different regimens. Int Conf AIDS. 1992; 8:B134.

178. Opravil M, Heald A, Lazzarin A et al. Combined prophylaxis of Pneumocystis carinii pneumonia and toxoplasmosis: prospective, randomized trial of dapsone + pyrimethamine vs. aerosolized pentamidine. The Swiss Group for Clinical Studies on AIDS. Int Conf AIDS. 1992; 8:B139.

179. Ogata-Arakaki D, Falloon J, Lavelle J et al. The safety of weekly dapsone and weekly dapsone + pyrimethamine as pneumocystis prophylaxis. Int Conf AIDS. 1990; 6:224.

180. Jacobus Pharmaceutical Company Inc. Dapsone tablets prescribing information. Princeton, NJ; 2009 Aug.

184. Danneman B, McCutchan JA, Israelski D et al. Treatment of toxoplasmic encephalitis in patients with AIDS: a randomized trial comparing pyrimethamine plus clindamycin to pyrimethamine plus sulfadiazine. Ann Intern Med. 1992; 116:33-43. [IDIS 289401] [PubMed 1727093]

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193. Remington JS, Vildé JL. Clindamycin for toxoplasma encephalitis in AIDS. Lancet. 1991; 338:1142-3.

194. Luft BJ, Hafner R, Korzun AH et al. Toxoplasma encephalitis in patients with the acquired immunodeficiency syndrome. N Engl J Med. 1993; 329:995-1000. [IDIS 320202] [PubMed 8366923]

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