Class: Antimalarials
VA Class: AP101
CAS Number: 58-14-0
Brands: Daraprim, Fansidar
- Fixed Combination of Sulfadoxine and Pyrimethamine (Fansidar )
Severe reactions (e.g., Stevens-Johnson syndrome, toxic epidermal necrolysis), including fatalities, reported.168 (See Dermatologic and Hypersensitivity Reactions under Cautions.)
Discontinue at first sign of rash, significant myelosuppression, or active bacterial or fungal infection.168
Introduction
Antimalarial and antiparasitic agent; folic acid antagonist.167 168 a Pyrimethamine commercially available as single-entity preparation or in fixed combination with sulfadoxine (Fansidar).167 168
Uses for Pyrimethamine, Sulfadoxine and Pyrimethamine
Malaria
Pyrimethamine (single-entity preparation)167 and fixed-combination preparation containing sulfadoxine and pyrimethamine (Fansidar)104 128 139 168 186 188 have been used for prevention (prophylaxis) of malaria, but are no longer recommended by CDC or others for malaria prevention.203 212 b c Resistance to pyrimethamine is prevalent worldwide;167 resistance to Fansidar is widespread in certain areas (e.g., Amazon basin area of South America, Southeast Asia, other parts of Asia, large parts of Africa).203 b Consider use of Fansidar for malaria prophylaxis only in individuals traveling to areas where chloroquine-resistant Plasmodium falciparum malaria is endemic and susceptible to the drug and only when other antimalarials (chloroquine, mefloquine, doxycycline, fixed combination of atovaquone and proguanil hydrochloride [Malarone]) are unavailable or contraindicated.168
Although pyrimethamine (single-entity preparation) has been used in conjunction with a sulfonamide for treatment of acute malaria, it should not be used alone167 and is not included in current CDC recommendations for treatment of malaria.c Fansidar has been used in conjunction with oral quinine sulfate for treatment of uncomplicated or mild to moderate malaria caused by chloroquine-resistant P. falciparum,186 187 189 but is not included in current CDC recommendations for treatment of uncomplicated or severe malaria.c
Fansidar has been used for presumptive self-treatment of malaria† in travelers without sulfonamide sensitivity traveling to areas where resistance to the drug has not been reported,188 189 208 b but CDC generally recommends the fixed combination of atovaquone and proguanil (Malarone) for such treatment.203 b
Detailed recommendations regarding prevention of malaria available from CDC at 877-394-8747 or .b
Assistance with diagnosis or treatment of malaria available from CDC Malaria Epidemiology Branch by contacting CDC Malaria Hotline at 770-488-7788 from 8:00 a.m. to 4:30 p.m. Eastern Standard Time, CDC Emergency Operation Center at 770-488-7100 after hours, on weekends, and holidays or at .b
Pneumocystis jiroveci (Pneumocystis carinii) Pneumonia
Pyrimethamine (single-entity preparation) and leucovorin used in conjunction with dapsone for prevention of of Pneumocystis jiroveci (formerly Pneumocystis carinii) pneumonia† (PCP).171 172 173 174 175 176 177 178 179 180 196 199 203 208 214 Pyrimethamine and Fansidar are not included in current CDC, NIH, and IDSA recommendations for treatment of PCP.214 215
Pyrimethamine and leucovorin used in conjunction with dapsone is one of several alternatives that can be used for prevention of initial episodes of PCP (primary prophylaxis)† in HIV-infected adults and adolescents when co-trimoxazole (the drug of choice) cannot be used.199 203 208 Only limited data available regarding use of this regimen for such prophylaxis in children.d
Pyrimethamine and leucovorin used in conjunction with dapsone is one of several alternatives that can be used for long-term suppressive or chronic maintenance therapy (secondary prophylaxis) of PCP† in HIV-infected adults and adolescents when co-trimoxazole (the drug of choice) cannot be used.199 203 208 214 Only limited data available regarding use of this regimen for such prophylaxis in children.d
Although Fansidar has been used for prophylaxis of PCP† in HIV-infected individuals, including those who do not tolerate co-trimoxazole prophylaxis,128 129 130 131 134 135 136 146 165 166 180 183 203 the drug is not recommended by USPHS/IDSA, CDC, NIH, or others as a preferred or alternative drug for prevention of PCP.180 199 203 214
Toxoplasmosis
Pyrimethamine (single-entity preparation) is used in conjunction with other anti-infectives for treatment or prevention† of toxoplasmosis caused by Toxoplasma gondii.167 199 214 215
Pyrimethamine and leucovorin used in conjunction with sulfadiazine is the regimen of choice for initial treatment of toxoplasmosis in adults, adolescents, or children, including HIV-infected individuals.184 185 203 208 214 215
Pyrimethamine and leucovorin used in conjunction with clindamycin is a preferred alternative for treatment of toxoplasmosis in immunocompromised adults, adolescents, or children who are unable to tolerate the sulfonamide component of the regimen of choice or have failed to respond to or have relapsed after the treatment of choice.152 153 154 155 158 164 184 193 194 198 203 208 214 215 Pyrimethamine and leucovorin used in conjunction with atovaquone or azithromycin also are alternatives for treatment of toxoplasmosis in adults and adolescents when the regimen of choice cannot be used; these regimens have not been studied in children.214 When a parenteral regimen is indicated, some experts suggest use of oral pyrimethamine in conjunction with parenteral co-trimoxazole or parenteral clindamycin.214
Pyrimethamine and leucovorin used in conjunction with sulfadiazine is the regimen of choice for treatment of symptomatic or asymptomatic congenital toxoplasmosis.208 215 Empiric treatment of the infant should be strongly considered if the mother had symptomatic Toxoplasma infection during pregnancy, even if the mother was treated.215
Pyrimethamine and leucovorin used in conjunction with dapsone is the recommended alternative regimen for prevention of T. gondii encephalitis (primary prophylaxis)† in HIV-infected adults, adolescents, and children when the regimen of choice (co-trimoxazole) cannot be used.178 195 199 210 211 Pyrimethamine and leucovorin used in conjunction with atovaquone is another alternative for primary prophylaxis of toxoplasmosis in HIV-infected adults and adolescents when the regimen of choice (co-trimoxazole) cannot be used.199 203
Pyrimethamine and leucovorin used in conjunction with sulfadiazine is the regimen of choice for long-term suppressive or chronic maintenance therapy (secondary prophylaxis) to prevent relapse of T. gondii encephalitis† in HIV-infected adults, adolescents, or children who have completed treatment for the disease.199 214 215
Pyrimethamine and leucovorin in conjunction with clindamycin is an alternative in adults, adolescents, or children and pyrimethamine and leucovorin used in conjunction with atovaquone is an alternative in adults and adolescents for secondary prophylaxis of toxoplasmosis in HIV-infected individuals when the regimen of choice cannot be used.199 214
Isosporiasis
Pyrimethamine (single-entity preparation) has been used for treatment of isosporiasis† caused by Isospora belli in certain patients, including HIV-infected individuals, when the drug of choice (co-trimoxazole) could not be used (e.g., because of sulfonamide sensitivity).192 214
Pyrimethamine, Sulfadoxine and Pyrimethamine Dosage and Administration
Administration
Oral Administration
Pyrimethamine (single-entity preparation): Administer orally.167 If anorexia or vomiting occurs, give with a meal to minimize adverse GI effects.167
Fixed combination containing pyrimethamine and sulfadoxine (Fansidar): Administer orally with plenty of fluids after a meal.168 Swallow whole; do not chew.168
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
Dosage of Fansidar is given in terms of number of tablets.168 Each tablet contains 500 mg of sulfadoxine and 25 mg of pyrimethamine.168
Pediatric Patients
Malaria (Pyrimethamine)
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
Consider that resistance to pyrimethamine is prevalent worldwide.167 (See Malaria under Uses.)
Treatment of 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
Consider that resistance to pyrimethamine is prevalent worldwide.167 (See Malaria under Uses.)
Malaria (Fansidar)
Prevention of Malaria
Oral
Weight (kg) | Dosage (Once Weekly) |
|---|---|
5–10 | 0.25 tablet |
11–20 | 0.5 tablet |
21–30 | 0.75 tablet |
31–45 | 1 tablet |
>45 | 1.5 tablets |
Initiate prophylaxis 1 or 2 days prior to entering a malarious area and continue for 4–6 weeks after leaving the area.168 If there are concerns about tolerance or drug interactions, it may be advisable to initiate prophylaxis sooner prior to travel in individuals receiving other drugs to ensure that the combination of drugs is well tolerated and to allow ample time if a switch to another antimalarial is required.d
Terminal prophylaxis with primaquine may be indicated during the final 2 weeks or immediately following Fansidar prophylaxis if exposure occurred in areas where P. ovale or P. vivax are endemic.d
Consider that resistance to sulfadoxine and pyrimethamine has been reported.203 205 (See Malaria under Uses.)
Treatment of Uncomplicated P. falciparum Malaria
Oral
Weight (kg) | Dosage (Single Dose) |
|---|---|
5–10 | 0.5 tablet |
11–20 | 1 tablet |
21–30 | 1.5 tablets |
31–45 | 2 tablets |
>45 | 3 tablets |
Consider that resistance to sulfadoxine and pyrimethamine has been reported.203 205 (See Malaria under Uses.)
Pneumocystis jiroveci (Pneumocystis carinii) Pneumonia† (Pyrimethamine)
Prevention (Primary Prophylaxis)†
Oral
Adolescents: 50 mg once weekly with oral leucovorin (25 mg once weekly) in conjunction with oral dapsone (50 mg once daily).199 203 Alternatively, 75 mg once weekly with oral leucovorin (25 mg once weekly) in conjunction with oral dapsone (200 mg once weekly).199 203
Criteria for initiating or discontinuing primary PCP prophylaxis† in HIV-infected adolescents are the same as those recommended for adults.199 (See Adults under Dosage and Administration.)
Prevention of Recurrence (Secondary Prophylaxis)†
Oral
Adolescents: 50 mg once weekly with oral leucovorin (25 mg once weekly) in conjunction with oral dapsone (50 mg once daily).199 203 214 Alternatively, 75 mg once weekly with oral leucovorin (25 mg once weekly) in conjunction with oral dapsone (200 mg once weekly).199 203 214
Criteria for initiating or discontinuing secondary PCP prophylaxis in adolescents are the same as those recommended for adults.214 (See Adults under Dosage and Administration.)
Toxoplasmosis (Pyrimethamine)
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 (up to 50 mg) once daily for 2 days, then 1 mg/kg (up to 25 mg) once daily for 2–6 months, then 1 mg/kg 3 times weekly; used in conjunction with oral or IM leucovorin (10 mg with each pyrimethamine dose) and oral sulfadiazine (50 mg/kg twice daily).215
Optimal duration of treatment unclear and should be determined in consultation with an expert; treatment often is continued for 12 months.208 215
Treatment in HIV-infected Infants and Children
Oral
2 mg/kg (up to 50 mg) once daily for 3 days, then 1 mg/kg once daily; used in conjunction with oral leucovorin (10–25 mg once daily) and oral sulfadiazine (25–50 mg/kg 4 times daily).215 Alternatively, pyrimethamine 2 mg/kg once daily for 3 days, then 1 mg/kg once daily used in conjunction with oral leucovorin (10–25 mg once daily) and oral or IV clindamycin (5–7.5 mg/kg 4 times daily).215
Continue acute treatment for ≥6 weeks; a longer duration may be appropriate if disease is extensive or response incomplete at 6 weeks.215
Treatment in HIV-infected Adolescents
Oral
200 mg once, then 50 mg once daily in those weighing <60 kg or 75 mg once daily in those weighing ≥60 kg; used in conjunction with oral leucovorin (at least 10–20 mg once 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).214
Alternatively, 200 mg once, then 50 mg once daily in those weighing <60 kg or 75 mg once daily in those weighing ≥60 kg; used in conjunction with oral leucovorin (at least 10–20 mg once daily) and either 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).214
Continue acute treatment for ≥6 weeks; a longer duration may be appropriate if disease is extensive or response incomplete at 6 weeks.214
Prevention (Primary Prophylaxis) in HIV-Infected Infants and Children†
Oral
1 mg/kg once daily used in conjunction with oral leucovorin (5 mg once every 3 days) and dapsone (2 mg/kg or 15 mg/m2 once daily).199
Primary prophylaxis against T. gondii encephalitis should be initiated in all HIV-infected infants and children with severe immunosuppression who are seropositive for Toxoplasma IgG antibody.199 d
The safety of discontinuing primary toxoplasmosis prophylaxis in HIV-infected children receiving potent antiretroviral therapy has not been extensively studied to date.199
Prevention (Primary Prophylaxis) in HIV-Infected Adolescents†
Oral
50 mg once weekly used in conjunction with oral leucovorin (25 mg once weekly) with oral dapsone (50 mg once daily).199 Alternatively, 75 mg once weekly used in conjunction with oral leucovorin (25 mg once weekly) and oral dapsone (200 mg once weekly).199
Alternatively, 25 mg once daily used in conjunction with oral leucovorin (10 mg once daily) and oral atovaquone (1.5 g once daily).199
Criteria for initiating or discontinuing primary prophylaxis against toxoplasmosis in adolescents are the same as those recommended for adults.199 (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 in conjunction with oral leucovorin (5 mg once every 3 days) and either oral sulfadiazine (85–120 mg/kg daily in 2–4 divided doses) or, alternatively, oral clindamycin (20–30 mg/kg daily in 4 divided doses).199
Secondary prophylaxis against toxoplasmosis generally is continued for life.199 214 215 The safety of discontinuing secondary toxoplasmosis prophylaxis in HIV-infected infants and children receiving potent antiretroviral therapy has not been extensively studied.199 214 215
Prevention of Recurrence (Secondary Prophylaxis) in HIV-infected Adolescents†
Oral
Dosage for secondary prophylaxis against toxoplasmosis in adolescents and criteria for initiation or discontinuance of such prophylaxis in this age group are the same as those recommended for adults.199 214 (See Adults under Dosage and Administration.)
Adults
Malaria (Pyrimethamine)
Prevention of Malaria
Oral
Manufacturer recommends 25 mg once weekly.167
Consider that resistance to pyrimethamine is prevalent worldwide.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
Consider that resistance to pyrimethamine is prevalent worldwide.167 (See Malaria under Uses.)
Malaria (Fansidar)
Prevention of Malaria
Oral
Fansidar: 1 tablet once weekly or 2 tablets once every 2 weeks.168
Initiate prophylaxis 1 or 2 days prior to entering a malarious area and continue for 4–6 weeks after leaving the area.168 If there are concerns about tolerance or drug interactions, it may be advisable to initiate prophylaxis sooner prior to travel in individuals receiving other drugs to ensure that the combination of drugs is well tolerated and to allow ample time if a switch to another antimalarial is required.b
Terminal prophylaxis with primaquine may be indicated during the final 2 weeks or immediately following Fansidar prophylaxis if exposure occurred in areas where P. ovale or P. vivax are endemic.b
Consider that resistance to sulfadoxine and pyrimethamine has been reported.203 205 (See Malaria under Uses.)
Treatment of Uncomplicated P. falciparum Malaria
Oral
Fansidar: 2–3 tablets as a single dose.168
For treatment of chloroquine-resistant P. falciparum malaria, single Fansidar dose has been used in conjunction with a quinine regimen given for 3–7 days;189 administer Fansidar dose on last day of quinine therapy.189
Pneumocystis jiroveci (Pneumocystis carinii) Pneumonia† (Pyrimethamine)
Prevention (Primary Prophylaxis)†
Oral
50 mg once weekly used in conjunction with oral leucovorin (25 mg once weekly) and oral dapsone (50 mg once daily).199 203 214 Alternatively, 75 mg once weekly used in conjunction with oral leucovorin (25 mg once weekly) and oral dapsone (200 mg once weekly).199 203 214
Initiate primary prophylaxis against PCP in HIV-infected adults and adolescents with CD4+ T-cell counts <200/mm3 or a history of oropharyngeal candidiasis.199 Also consider primary prophylaxis if CD4+ T-cell percentage is <14% or there is a history of an AIDS-defining illness.199
Primary prophylaxis can be discontinued in adults and adolescents responding to potent antiretroviral therapy who have a sustained (3 months or longer) increase in CD4+ T-cell counts from <200/mm3 to >200/mm3.199
Reinitiate primary prophylaxis if CD4+ T-cell count decreases to <200/mm3.199
Prevention of Recurrence (Secondary Prophylaxis)†
Oral
50 mg once weekly used in conjunction with oral leucovorin (25 mg once weekly) and oral dapsone (50 mg once daily).199 203 214 Alternatively, 75 mg once weekly used in conjunction with oral leucovorin (25 mg once weekly) and oral dapsone (200 mg once weekly).199 203 214
Initiate long-term suppressive therapy or chronic maintenance therapy (secondary prophylaxis) to prevent recurrence in those with a history of PCP.199 214
Discontinuance of secondary prophylaxis is recommended in those who have a sustained (3 months or longer) increase in CD4+ T-cell counts to >200/mm3199 214 since such prophylaxis appears to add little benefit in terms of disease prevention and discontinuance reduces medication burden, potential for toxicity, drug interactions, selection of drug-resistant pathogens, and cost.199
Reinitiate secondary prophylaxis if CD4+ T-cell count decreases to <200/mm3 or if PCP recurs at a CD4+ T-cell count >200/mm3.199 214 It probably is prudent to continue secondary prophylaxis for life in those who had PCP episodes when they had CD4+ T-cell counts >200/mm3.199
Toxoplasmosis (Pyrimethamine)
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 once, then 50 mg once daily in those weighing <60 kg or 75 mg once daily in those weighing ≥60 kg; used in conjunction with oral leucovorin (at least 10–20 mg once 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).214
Alternatively, 200 mg once daily, then 50 mg once daily in those weighing <60 kg or 75 mg once daily in those weighing ≥60 kg; used in conjunction with oral leucovorin (at least 10–20 mg once daily) and either 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).214
Continue acute treatment for ≥6 weeks; a longer duration may be appropriate if disease is extensive or response incomplete at 6 weeks.214
Prevention (Primary Prophylaxis) in HIV-Infected Adults†
Oral
50 mg once weekly used in conjunction with oral leucovorin (25 mg once weekly) and oral dapsone (50 mg once daily).199 Alternatively, 75 mg once weekly used in conjunction with oral leucovorin (25 mg once weekly) and oral dapsone (200 mg once weekly).199
Alternatively, 25 mg once daily used in conjunction with oral leucovorin (10 mg once daily) and oral atovaquone (1.5 g once daily).199
Discontinuance of primary toxoplasmosis prophylaxis is recommended in HIV-infected adults and adolescents who have a sustained (3 months or longer) increase in CD4+ T-cell counts to >200/ mm3 since such prophylaxis appears to add little benefit in terms of disease prevention and discontinuance reduces medication burden, potential for toxicity, drug interactions, selection of drug-resistant pathogens, and cost.199
Reinitiate primary prophylaxis if CD4+ T-cell count decreases to <100–200/mm3.199
Prevention of Recurrence (Secondary Prophylaxis) in HIV-infected Adults†
Oral
25–50 mg once daily in conjunction with oral leucovorin (10–25 mg once daily) and either oral sulfadiazine (0.5–1 g every 6 hours) or, alternatively, oral clindamycin (300–450 mg every 6–8 hours).199 214
Alternatively, 25 mg once daily with oral leucovorin (10 mg once daily) and oral atovaquone (750 mg every 6–12 hours).199 214
Initiate long-term suppressive therapy or chronic maintenance therapy (secondary prophylaxis) in all patients who have completed initial treatment of toxoplasmosis encephalitis (TE).199 214
Consideration can be given to discontinuing secondary prophylaxis in adults or adolescents who successfully completed initial treatment for TE, are asymptomatic with respect to TE, and have a sustained (6 months or longer) increase in CD4+ T-cell counts to >200/mm3.199 214
Reinitiate secondary prophylaxis if CD4+ T-cell count decreases to <200/mm3.199 214
Isosporiasis† (Pyrimethamine)
Oral
50–75 mg once daily or in divided doses with oral leucovorin (5–10 mg) once daily.203 214
Prescribing Limits
Pediatric Patients
Toxoplasmosis (Pyrimethamine)
Treatment of HIV-infected Infants and Children
Oral
Maximum 25–50 mg per dose.215
Prevention of Recurrence (Secondary Prophylaxis) in HIV-infected Infants and Children†
Oral
Maximum 25 mg per dose.199
Special Populations
No special population dosage recommendation at this time.167 168
Cautions for Pyrimethamine, Sulfadoxine and Pyrimethamine
Contraindications
- Pyrimethamine
Hypersensitivity to pyrimethamine or any ingredient in the formulation.167
Megaloblastic anemia caused by folate deficiency.167
- Fixed Combination of Sulfadoxine and Pyrimethamine (Fansidar )
Hypersensitivity to pyrimethamine, sulfonamides, or any ingredient in the formulation.168
Megaloblastic anemia caused by folate deficiency.168
Repeated prophylactic (prolonged) use in patients with renal or hepatic failure or blood dyscrasias.168
Infants <2 months of age.168
Prophylaxis in pregnancy at term.168 (See Pregnancy under Cautions.)
Prophylaxis in nursing women.168 (See Lactation under Cautions.)
Warnings/Precautions
Warnings
Severe Reactions
Fatalities due to erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis reported with Fansidar;110 111 112 114 132 136 139 140 143 144 145 168 fatalities related to hypersensitivity, hepatocellular necrosis, agranulocytosis, aplastic anemia, and other blood dyscrasias reported with sulfonamides.111 112 132 138 140 168 (See Dermatologic and Hypersensitivity Reactions under Cautions.)
Discontinue pyrimethamine or Fansidar at first sign of rash, sore throat, fever, arthralgia, cough, shortness of breath, pallor, jaundice, or glossitis.167 168
Discontinue Fansidar if significant myelosuppression or active bacterial or fungal infection occurs.110 159 168
Hematologic Effects
Agranulocytosis, aplastic anemia, megaloblastic anemia, thrombocytopenia, leukopenia, hemolytic anemia, purpura, hypoprothrombinemia, methemoglobinemia, and eosinophilia reported with sulfonamides and/or with pyrimethamine.114 168
High pyrimethamine dosage may deplete folic acid stores and cause reversible bone marrow depression.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 or discontinue pyrimethamine or Fansidar if signs of folic or folinic acid deficiency occur.167 168 Perform CBCs twice weekly.167 (See Laboratory Monitoring under Cautions.)
Pyrimethamine dosage used for treatment of toxoplasmosis approaches toxic levels and is associated with adverse effects resulting from folic acid deficiency.167 a Megaloblastic anemia, leukopenia, thrombocytopenia, and pancytopenia reported.167 When pyrimethamine is used for treatment of toxoplasmosis, give leucovorin (folinic acid) concomitantly.167 203 (See Toxoplasmosis under Pediatric Patients and also under Adults, in Dosage and Administration.) Adverse hematologic effects, including megaloblastic anemia, generally reversible when drug discontinued.a
Leukopenia (generally mild and reversible) reported when Fansidar administered for ≥2 months for malaria prevention.168
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
Fatalities due to erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis reported with Fansidar.110 111 112 114 132 136 139 140 143 144 145 159 168 Other hypersensitivity reactions, including serum-sickness reactions,168 vasculitis (cutaneous or generalized),140 urticaria,168 pruritus,140 168 exfoliative dermatitis,132 168 and photosensitivity,140 168 also reported.
Erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, and anaphylaxis reported with pyrimethamine single-entity preparation, especially when used with a sulfonamide.167 Periorbital edema,168 conjunctival and scleral injection,168 arthralgia,168 allergic myocarditis,168 slight hair loss,168 Lyell’s syndrome,168 allergic pericarditis,168 pulmonary eosinophilia,167 and pulmonary infiltrates resembling eosinophilic or allergic alveolitis also reported in patients receiving a sulfonamide or pyrimethamine.168
Use Fansidar with caution in patients with severe allergy or bronchial asthma.168
Avoid excessive sun exposure when taking Fansidar.168
Discontinue at first sign of rash, sore throat, fever, arthralgia, cough, shortness of breath, pallor, jaundice, or glossitis.167 168
General Precautions
Precautions Related to Prevention or Treatment of Malaria
Pyrimethamine and Fansidar are not included in current CDC recommendations for prevention or treatment of malaria.b c Consider that resistance to pyrimethamine is prevalent worldwide167 and resistance to Fansidar is widespread in certain areas.203 b (See Malaria under Uses.)
Do not use Fansidar for treatment of severe malaria.168 Has not been evaluated for treatment of cerebral malaria or other severe manifestations of complicated malaria, including hyperparasitemia, pulmonary edema, or renal failure.168 Patients with severe malaria are not candidates for oral therapy.168
If recrudescent P. falciparum infections occur after treatment with Fansidar or if prophylaxis with the drug fails, use a different blood schizonticide.168
Patients with G6PD Deficiency
Hemolysis may occur if Fansidar is used in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency.168 e
Renal Effects
Renal failure, hematuria, interstitial nephritis, elevated BUN and serum creatinine, toxic nephrosis with oliguria and anuria, and crystalluria reported in patients receiving a sulfonamide or pyrimethamine.167 168
Fansidar contains a sulfonamide and shares the toxic potentials of the sulfonamides.168 Sulfonamides have been associated with renal toxicity manifested by renal colic, nephritis, urolithiasis, toxic nephrosis with anuria and oliguria, hematuria, proteinuria, crystalluria, kidney stone formation, and elevation of BUN and serum creatinine concentrations.e Nephritis and hemolytic-uremic syndrome also reported.e
Adverse renal effects usually are the result of crystalluria.e Risk of crystalluria may be decreased by maintaining an adequate urinary output and by increasing urinary pH.e Unless the urine is highly acidic and/or the drug is relatively insoluble, alkalinization of the urine usually is not necessary if urinary output is maintained at a minimum of 1.5 L daily.e
Perform urinalysis and assess kidney function frequently during sulfonamide therapy.e Perform urinalysis (including microscopic examination) and renal function tests when Fansidar is used in patients with impaired renal function.168 (See Laboratory Monitoring under Cautions.) Maintain adequate fluid intake to minimize risk of crystalluria and stone formation.168 e
If persistent, heavy crystalluria, hematuria, or oliguria occurs, sulfonamide therapy should be discontinued and alkali therapy maintained.e
Hepatic Effects
Abnormal liver function test results (e.g., elevated serum ALT, AST, alkaline phosphatase, and bilirubin concentrations),132 140 141 142 jaundice,113 114 132 140 142 hepatomegaly,132 and hepatitis,132 142 168 sometimes fatal,132 reported with Fansidar.
Adverse hepatic effects have been associated with severe cutaneous reactions to Fansidar.112 132 (See Dermatologic and Hypersensitivity Reactions under Cautions.)
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, seizures, and respiratory failure reported with high pyrimethamine dosage.a Headache, light-headedness, insomnia, depression, malaise, fatigue, and irritability also reported rarely.a
In patients with seizure disorders being treated for toxoplasmosis, use low initial pyrimethamine dosage to avoid potential nervous system toxicity.167
Reversible hyperesthesia reported rarely with Fansidar.140
Laboratory Monitoring
Monitor CBC, including platelet counts, twice weekly in patients receiving high pyrimethamine dosage.167
If Fansidar is used for >3 months, regularly monitor liver enzyme tests, CBCs, and urinalysis for crystalluria.168 If used in patients with impaired renal function, monitor renal function and regularly perform urinalysis (including microscopic examination).168
Use of Fixed Combinations
When pyrimethamine is used in fixed combination with sulfadoxine, consider the cautions, precautions, and contraindications associated with sulfadoxine.168
Specific Populations
Pregnancy
Category C.167 168
Fansidar contraindicated for malaria prophylaxis in pregnant women at term.168
Use pyrimethamine or Fansidar during pregnancy only when potential benefits outweigh possible risks;167 168 if pyrimethamine is used to treat toxoplasmosis during pregnancy, administer leucovorin concurrently to decrease hematologic toxicity.167 197
Women of childbearing potential should use effective contraceptive measures while receiving pyrimethamine or Fansidar;167 168 avoid pregnancy for 3 months following the last dose of the fixed combination.
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