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Pyrimethamine, Sulfadoxine and Pyrimethamine

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

Warning(s)

  • 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

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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
Prevention of Malaria in Children >2 Months of Age (Fansidar).168

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
Treatment of Uncomplicated P. falciparum Malaria in Children >2 Months of Age (Fansidar).168

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.168

Lactation

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

Fansidar should not be used in nursing women because of the risk of sulfadoxine-induced kernicterus in the infant.116 168

Pediatric Use

Fansidar is contraindicated in children <2 months of age.168

Kernicterus, caused by displacement of bilirubin from protein binding sites, has occurred in neonates treated with sulfonamides.e

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

Geriatric Use

Pyrimethamine or Fansidar: Insufficient experience in patients ≥65 years of age to determine if they respond differently than younger adults; clinical experience has not identified differences.167 168

Select dosage with caution because of possible age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.167 168

Monitor renal function and adjust dosage of Fansidar with caution.168

Hepatic Impairment

Use Fansidar with caution in patients with impaired hepatic function.168 (See Hepatic Effects under Cautions.)

Renal Impairment

Use Fansidar with caution in patients with impaired renal function.168 Monitor renal function.168 (See Renal Effects under Cautions.)

Common Adverse Effects

Hypersensitivity reactions, GI effects, myelosuppression.167 168

Interactions for Pyrimethamine, Sulfadoxine and Pyrimethamine

Specific Drugs

Drug

Interaction

Comments

Anticoagulants, oral (warfarin)

Possibility that sulfonamide component of Fansidar may potentiate the effects of coumarin anticoagulants by displacing them from their protein-binding sites or by impairing anticoagulant metabolisme

Monitor PT or INR closelye

Chloroquine

Increased incidence and severity of adverse effects reported when Fansidar used with chloroquine168

Co-trimoxazole

Risk of adverse hematologic effects168

Discontinue Fansidar if signs of folate deficiency develop; 168 administer leucovorin until normal hematopoiesis restored168

Dapsone

Additive adverse hematologic effects; increased risk of agranulocytosisf

Monitor more frequently than usual for adverse hematologic effectsf

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

Because pyrimethamine and sulfonamides interfere with folic acid synthesis in susceptible organisms, this synergism is used to therapeutic advantage in the treatment of toxoplasmosis168 and has been used to therapeutic advantage in the prevention or treatment of malaria167 168 187 186 188 189 203 205 208 212

Increased risk of bone marrow suppression if pyrimethamine or Fansidar is used with other folic acid antagonists167 168

Pyrimethamine is used in conjunction with sulfadiazine for treatment of toxoplasmosis184 185 203 208 214 215

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

Concomitant use with antifolate agents other than sulfadiazine or sulfadoxine not recommended167 168

If signs of folate deficiency develop, discontinue pyrimethamine or Fansidar and administer leucovorin until normal hematopoiesis restored167 168

Lorazepam

Mild hepatotoxicity reported when pyrimethamine and lorazepam used concomitantly167

Methotrexate

Concomitant use of pyrimethamine and methotrexate may increase risk of bone marrow suppression167

If Fansidar used, possibility that sulfonamide component may potentiate the effects of methotrexate by displacing it from protein-binding sites or inhibiting renal tubular secretion of methotrexatee

Use with cautione

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

NSAIAs (indomethacin)

Possibility that NSAIAs may displace the sulfonamide component of Fansidar from plasma albumin and increase concentrations of free drug in plasmae

Observe patient for possible adverse effectse

p-Aminobenzoic acid (PABA) and derivatives

PABA may interfere with pyrimethamine mechanism of actiona

Clinical importance unclear; probably should not be used in patients receiving pyrimethaminea

Phenytoin

May decrease 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

Salicylates

Possibility that salicylates may displace the sulfonamide component of Fansidar from plasma albumin and increase concentrations of free drug in plasmae

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

Pyrimethamine: Well absorbed from GI tract.167 168 Peak serum pyrimethamine concentrations attained within 2–6 hours.167

Fansidar: Peak plasma concentrations of pyrimethamine attained within 1.5–8 hours, and peak plasma concentrations of sulfadoxine attained within 2.5–6 hours.a

Distribution

Extent

Pyrimethamine distributed mainly to kidneys, lungs, liver, and spleen.104 105 Sulfadoxine widely distributed in the body.a

Pyrimethamine and sulfadoxine cross the placenta.167 168

Pyrimethamine and sulfadoxine distributed into milk.167 168

Plasma Protein Binding

Pyrimethamine: Approximately 80–90%.104 167 168

Sulfadoxine: Approximately 90%.168

Elimination

Metabolism

Pyrimethamine: Metabolized to several unidentified metabolites.168

Sulfadoxine: 5% of dose present in plasma as acetylated metabolite and 2–3% present as glucuronide.168

Elimination Route

Pyrimethamine and sulfadoxine principally eliminated by kidneys.168

Half-life

Pyrimethamine: Half-life averages 111 hours.a

Sulfadoxine: Half-life averages169 hours.a

Special Populations

Half-life of pyrimethamine and sulfadoxine may be prolonged in renal failure patients.168

Stability

Storage

Oral

Tablets

Pyrimethamine: 15–25°C in tight, light resistant container.108 167

Fansidar: Well-closed, light resistant container.108

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

  • Pyrimethamine inhibits folic acid synthesis by reversibly inhibiting dihydrofolate reductase.168

  • Sulfadoxine inhibits folic acid synthesis by inhibiting dihydropteroate synthase.168

  • Pyrimethamine and Fansidar are blood schizonticidal agents active against asexual erythrocytic forms of susceptible plasmodia.168

  • Pyrimethamine and Fansidar are active against Toxoplasma gondii.a

  • Pyrimethamine resistance may be induced in plasmodia and frequently occurs in areas where the drug has been widely used.a Pyrimethamine resistance reported in Plasmodium vivax, P. malariae, and P. falciparum malaria.a P. falciparum with pyrimethamine-resistance also may be cross-resistant to chloroquine and hydroxychloroquine.a

  • P. falciparum resistant to pyrimethamine and/or chloroquine may be susceptible to Fansidar.a P. falciparum resistant to Fansidar is widespread in the Amazon River basin area of South America, southeast Asia and other parts of Asia, and increasingly in large parts of Africa;b Fansidar resistance also reported in Bangladesh and Oceania.203

Advice to Patients

  • Advise patient to discontinue pyrimethamine or Fansidar and inform clinicians at the first appearance of rash, sore throat, fever, arthralgia, cough, shortness of breath, pallor, purpura, jaundice, or glossitis.167 168

  • Importance of discontinuing Fansidar if bacterial or fungal infection occurs.168

  • Advise patient receiving Fansidar to maintain adequate fluid intake to prevent crystalluria and stone formation.168

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

  • Advise patients that photosensitivity has been reported with sulfonamides and they should avoid exposure to UV light or prolonged exposure to sunlight when taking Fansidar.b 168

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.116

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.116 167 168 (See Pregnancy under Cautions.)

  • Importance of informing patients of other important precautionary information.116 (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)

GlaxoSmithKline

Sulfadoxine and Pyrimethamine

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

Sulfadoxine 500 mg and Pyrimethamine 25 mg

Fansidar (scored)

Roche

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions June 1, 2008. 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.

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