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Pyrimethamine

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

Medically reviewed by Drugs.com on February 23, 2021. Written by ASHP.

Introduction

Antimalarial and antiprotozoal agent; folic acid antagonist.

Uses for 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. 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.

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. Recommended by CDC, NIH, IDSA, and AAP as preferred alternative in those who cannot tolerate co-trimoxazole.

Malaria

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

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

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. 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); severe and sometimes fatal adverse reactions reported when fixed combination used for malaria prevention (see Dermatologic and Hypersensitivity Reactions under Cautions). Fixed combination no longer commercially available in US and not included in CDC recommendations for prevention or treatment of malaria. Fixed combination may still be used for treatment of uncomplicated P. falciparum malaria in some countries where the disease is endemic, usually in conjunction with artesunate in artemisinin-based combination therapy (ACT).

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].

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.

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.

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.

Co-trimoxazole generally drug of choice for primary and secondary prophylaxis of PCP in HIV-infected adults, adolescents, and children.

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).

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

Toxoplasmosis

Pyrimethamine (and leucovorin) used in conjunction with sulfadiazine, clindamycin, atovaquone, or azithromycin for treatment of toxoplasmosis caused by Toxoplasma gondii.

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.

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. 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; these regimens not studied in children.

Pyrimethamine (and leucovorin) used in conjunction with sulfadiazine is the regimen of choice for treatment of congenital toxoplasmosis. 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.

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. 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.

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.

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; pyrimethamine (and leucovorin) used in conjunction with atovaquone is another alternative in HIV-infected adults and adolescents.

Pyrimethamine Dosage and Administration

Administration

Oral Administration

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

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. (See Stability.) Shake oral suspension prior to each dose.

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.

Treatment in HIV-infected Adolescents†
Oral

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

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).

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).

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

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

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.

Malaria
Prevention of Malaria
Oral

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

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

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

Pyrimethamine-resistant strains prevalent worldwide; not suitable for prevention of malaria in most areas. (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.

Pyrimethamine-resistant strains prevalent worldwide; do not use alone for treatment of acute malaria. (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). Alternatively, 75 mg once weekly with oral leucovorin (25 mg once weekly) and oral dapsone (200 mg once weekly).

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

Criteria for initiating or discontinuing primary prophylaxis of PCP in HIV-infected adolescents are the same as those for adults. (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). Alternatively, 75 mg once weekly with oral leucovorin (25 mg once weekly) and oral dapsone (200 mg once weekly).

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

Criteria for initiating or discontinuing secondary prophylaxis of PCP in adolescents are the same as those for adults. (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. Must be used in conjunction with a sulfonamide.

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).

Recommended duration in HIV-infected infants is 12 months.

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). 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).

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

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).

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).

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

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.

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.

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%. 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.

Safety of discontinuing primary prophylaxis against toxoplasmosis in HIV-infected children whose immunologic status improves with potent antiretroviral therapy not extensively studied to date. Do not discontinue primary prophylaxis in HIV-infected children <1 year of age. 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. 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.

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.

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

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

Criteria for initiating or discontinuing primary prophylaxis against toxoplasmosis in adolescents are the same as those for adults. (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).

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.

Safety of discontinuing secondary prophylaxis against toxoplasmosis in HIV-infected children receiving potent antiretroviral therapy not extensively studied. 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.

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.

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).

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

Criteria for initiating or discontinuing secondary prophylaxis against toxoplasmosis in adolescents are the same as those for adults. (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).

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

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

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.

Malaria
Prevention of Malaria
Oral

Manufacturer recommends 25 mg once weekly.

Pyrimethamine-resistant strains prevalent worldwide; not suitable for prevention of malaria in most areas. (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.

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

Pyrimethamine-resistant strains prevalent worldwide; do not use alone for treatment of acute malaria. (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). Alternatively, 75 mg once weekly with oral leucovorin (25 mg once weekly) and oral dapsone (200 mg once weekly).

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

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

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.

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

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

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

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

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.

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

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.

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).

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).

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

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

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

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.

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

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).

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

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

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. 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.

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

Prescribing Limits

Pediatric Patients

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

Maximum 25 mg daily.

Toxoplasmosis
Treatment of HIV-infected Children
Oral

Maximum 25–50 mg per dose.

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

Maximum 25 mg per dose.

Special Populations

No special population dosage recommendation at this time.

Cautions for Pyrimethamine

Contraindications

  • Hypersensitivity to pyrimethamine or any ingredient in the formulation.

  • Megaloblastic anemia caused by folate deficiency.

Warnings/Precautions

Warnings

Hematologic Effects

High pyrimethamine dosage may cause folic acid deficiency and cause reversible bone marrow depression. 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). Hematologic effects may also occur with lower pyrimethamine dosages in certain individuals.

Reduce dosage or discontinue if signs of folic or folinic acid deficiency occur. Perform CBCs twice weekly. (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. Megaloblastic anemia, leukopenia, thrombocytopenia, and pancytopenia reported. When pyrimethamine is used for treatment of toxoplasmosis, give leucovorin (folinic acid) concomitantly. (See Toxoplasmosis under Pediatric Patients and also under Adults, in Dosage and Administration.)

Carcinogenicity

Manufacturer states pyrimethamine may be carcinogenic. 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.

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.

Severe, sometimes fatal, hypersensitivity reactions have occurred in patients receiving fixed-combination preparation of sulfadoxine and pyrimethamine (sulfadoxine/pyrimethamine; Fansidar). In most reported cases, fatalities resulted from severe cutaneous reactions, including erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis. Pulmonary hypersensitivity reactions, fatal reaction involving the skin, liver, and kidneys, and fatal hepatitis also reported. The fixed-combination preparation no longer commercially available in US, but may still be available in other countries.

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

General Precautions

GI Effects

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

Nervous System Effects

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

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

Laboratory Monitoring

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

Specific Populations

Pregnancy

Category C.

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

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. 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.

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

Lactation

Pyrimethamine distributed into milk. Discontinue nursing or the drug, taking into account the importance of the drug to the woman.

Pediatric Use

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

Keep out of the reach of children.

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.

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

Common Adverse Effects

Hypersensitivity reactions, GI effects, myelosuppression.

Interactions for Pyrimethamine

Specific Drugs

Drug

Interaction

Comments

Dapsone

Additive adverse hematologic effects; increased risk of agranulocytosis

No clinically important effect on pyrimethamine pharmacokinetics

Monitor for adverse hematologic effects more frequently than usual

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 toxoplasmosis and has been used to therapeutic advantage in prevention or treatment of malaria

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

Pyrimethamine used in conjunction with sulfadiazine for treatment of toxoplasmosis

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

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

Lorazepam

Mild hepatotoxicity reported when pyrimethamine and lorazepam used concomitantly

Methotrexate

May increase risk of bone marrow suppression

Use with caution

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

Phenytoin

Decreased folic acid levels

Use with caution

Proguanil

May increase risk of bone marrow suppression

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

Zidovudine

May increase risk of bone marrow suppression

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

Pyrimethamine Pharmacokinetics

Absorption

Bioavailability

Well absorbed from GI tract; peak serum concentrations attained within 2–6 hours.

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

Distribution

Extent

Distributed mainly to kidneys, lungs, liver, and spleen.

Distributed into CSF.

Crosses the placenta.

Distributed into milk.

Plasma Protein Binding

Approximately 80–90%.

Elimination

Metabolism

Metabolized in the liver to several unidentified metabolites.

Elimination Route

Unchanged drug and metabolites eliminated principally by kidneys.

Half-life

Approximately 96 hours.

Special Populations

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

Stability

Storage

Oral

Tablets

15–25°C in tight, light resistant container.

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.

Actions

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

  • Blood schizonticidal agent active against asexual erythrocytic forms of susceptible P. falciparum, P. malariae, P. ovale, and P. vivax.

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

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

Advice to Patients

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

  • Advise patients not to exceed recommended dosage.

  • 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.

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

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

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

  • Importance of informing patients of other important precautionary information. (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.

Pyrimethamine

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

25 mg

Daraprim (scored)

Amedra

AHFS DI Essentials™. © Copyright 2021, Selected Revisions March 5, 2014. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

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

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