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Pyrimethamine

Medically reviewed by Drugs.com. Last updated on Apr 23, 2020.

Pronunciation

(peer i METH a meen)

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Daraprim: 25 mg [scored]

Generic: 25 mg

Brand Names: U.S.

  • Daraprim

Pharmacologic Category

  • Antimalarial Agent

Pharmacology

Inhibits parasitic dihydrofolate reductase, resulting in inhibition of vital tetrahydrofolic acid synthesis

Absorption

Well absorbed

Distribution

Vd: Adults: 2.9 L/kg; distributed to the kidneys, lung, liver, and spleen

Excretion

Urine (16% to 32%)

Time to Peak

Serum: 2 to 6 hours

Half-Life Elimination

80 to 95 hours (White 1985)

Protein Binding

87%

Use: Labeled Indications

Toxoplasmosis: Treatment of toxoplasmosis (in combination with a sulfonamide).

Off Label Uses

Cystoisosporiasis (formerly Isosporiasis) in patients with HIV

Based on the US Department of Health and Human Services (HHS) Guidelines for Prevention and Treatment of Opportunistic Infections in Adults and Adolescents with HIV, pyrimethamine in combination with leucovorin is an effective and recommended alternative agent in the treatment of or as chronic suppressive therapy of Cystoisosporiasis (formerly Isosporiasis) infection in patients with HIV.

Pneumocystis pneumonia in patients with HIV

Based on the US HHS Guidelines for Prevention and Treatment of Opportunistic Infections in Adults and Adolescents with HIV, pyrimethamine in combination with leucovorin (and dapsone or atovaquone) is an effective and recommended alternative agent in the primary prophylaxis of or as chronic maintenance (secondary prophylaxis) of Pneumocystis pneumonia in patients with HIV.

Toxoplasma gondii encephalitis (treatment/primary prophylaxis/chronic maintenance therapy) in patients with HIV

Based on the US HHS Guidelines for Prevention and Treatment of Opportunistic Infections in Adults and Adolescents with HIV, pyrimethamine in combination with leucovorin and other agents is an effective and recommended agent in the treatment of or as chronic maintenance (secondary prophylaxis) of Toxoplasma gondii encephalitis, and is a recommended alternative agent in combination with leucovorin and other agents for primary prophylaxis of Toxoplasma gondii encephalitis in patients with HIV.

Contraindications

Hypersensitivity to pyrimethamine or any component of the formulation; megaloblastic anemia secondary to folate deficiency

Dosing: Adult

Cystoisosporiasis (formerly Isosporiasis) in patients with HIV (alternative agent) (off-label use) (HHS [OI adult 2020]): Oral:

Treatment: 50 to 75 mg once daily in combination with leucovorin calcium.

Chronic maintenance (secondary prophylaxis): 25 mg once daily in combination with leucovorin calcium.

Pneumocystis pneumonia in patients with HIV (alternative agent) (off-label use) (HHS [OI adult 2020]): Oral:

Primary prophylaxis: 50 or 75 mg once weekly in combination with dapsone and leucovorin calcium; or 25 mg once daily in combination with atovaquone and leucovorin calcium.

Chronic maintenance (secondary prophylaxis): 50 to 75 mg once weekly in combination with dapsone and leucovorin calcium; or 25 mg once daily in combination with atovaquone and leucovorin calcium.

Duration of therapy: Continue until CD4 count >200 cells/mm3 for >3 months in response to antiretroviral therapy; some experts discontinue prophylaxis in patients with CD4 counts between 100 and 200 cells/mm3 who are receiving antiretroviral therapy (ART) and have had an undetectable viral load for ≥3 to 6 months (HHS [OI adult 2020]).

Toxoplasmosis treatment: Oral: 50 to 75 mg/day for 1 to 3 weeks depending on patient's tolerance and response, then may reduce dose by 50% and continue for 4 to 5 weeks; use with a sulfonamide in combination with leucovorin calcium

Toxoplasmosis in patients with HIV (off label) (HHS [OI adult 2020]): Oral:

Primary prophylaxis (alternative agent): 50 or 75 mg once weekly in combination with dapsone and leucovorin calcium; or 25 mg once daily in combination with atovaquone and leucovorin calcium. Continue until CD4 count >200 cells/mm3 for >3 months in response to ART; some experts discontinue prophylaxis in patients with CD4 counts between 100 and 200 cells/mm3 who are receiving ART and have had an undetectable viral load for ≥3 to 6 months.

Chronic maintenance therapy (secondary prophylaxis): 25 to 50 mg once daily in combination with sulfadiazine and leucovorin calcium; or 25 to 50 mg once daily in combination with clindamycin and leucovorin calcium (alternative regimen); or 25 mg once daily in combination with atovaquone and leucovorin calcium (alternative regimen).

Treatment of Toxoplasma gondii encephalitis: 200 mg as a single dose, followed by 50 mg (<60 kg) or 75 mg (≥60 kg) daily, in combination with sulfadiazine and leucovorin calcium for at least 6 weeks; or 200 mg as a single dose, followed by 50 mg (<60 kg) or 75 mg (≥60 kg) daily in combination with leucovorin calcium plus clindamycin or atovaquone (alternative regimens). Note: Pyrimethamine is no longer available in retail pharmacies in the US and is only available through a special pharmacy program. According to the HHS Guidelines for the prevention and treatment of opportunistic infections in adults and adolescents with HIV, if there is a delay in procuring pyrimethamine for patients with suspected or documented toxoplasmosis who do not have a history of sulfa allergy, trimethoprim-sulfamethoxazole should be used in place of pyrimethamine-containing regimens until pyrimethamine is available.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Note: Oral leucovorin should be administered throughout the entire course to prevent hematologic toxicity (AAP [Red Book 2018]; HHS [OI pediatric 2019]).

Cystoisosporiasis (formerly isosporiasis), HIV-exposed/-infected: Alternative therapy to sulfamethoxazole/trimethoprim.

Treatment:

Infants and Children: Oral: 1 mg/kg/day once daily in combination with leucovorin for 14 days; maximum daily dose: 25 mg/day (HHS [OI pediatric 2019]).

Adolescents: Oral: 50 to 75 mg once daily in combination with leucovorin (HHS [OI adult 2019]).

Chronic maintenance (secondary prophylaxis):

Infants and Children: Oral: 1 mg/kg/day once daily in combination with leucovorin; maximum daily dose: 25 mg/day (HHS [OI pediatric 2019]).

Adolescents: Oral: 25 mg once daily in combination with leucovorin (HHS [OI adult 2019]).

Pneumocystis jirovecii pneumonia (PCP) (HIV-exposed/-positive); primary prophylaxis or chronic maintenance (secondary prophylaxis): Alternative therapy (HHS [OI adult 2019]):

Adolescents: Oral:

In combination with dapsone and leucovorin: 50 to 75 mg once weekly (dose depends on dapsone dose).

In combination with atovaquone and leucovorin: 25 mg once daily.

Toxoplasmosis, acquired infection (including encephalitis); treatment:

HIV-exposed/-infected:

Infants and Children: Oral: 2 mg/kg/day (maximum dose: 50 mg/dose) once daily for 3 days followed by 1 mg/kg/day once daily (maximum dose: 25 mg/dose) in combination with leucovorin and either sulfadiazine or clindamycin; treat for at least 6 weeks; consider longer duration if clinical or radiologic disease is extensive or incomplete response; follow with chronic suppressive therapy in patients experiencing encephalitis (HHS [OI pediatric 2019]).

Adolescents: Oral: Encephalitis: 200 mg once as a single dose, followed by weight-based daily dosing; treat for at least 6 weeks (HHS [OI adult 2019]):

Weight <60 kg: 50 mg once daily.

Weight ≥60 kg: 75 mg once daily.

Non-HIV-exposed/-infected (Red Book [AAP 2018]):

Note: Use in combination with leucovorin and either sulfadiazine or clindamycin.

Infants, Children, and Adolescents:

<60 kg: Oral: Initial: 2 mg/kg/day in divided doses twice daily for 2 days (maximum dose: Chorioretinitis: 25 mg/dose; severe or CNS disease: 50 mg/dose); followed by 1 mg/kg/day once daily (maximum dose: Chorioretinitis: 25 mg/dose; severe or CNS disease: 50 mg/dose). Continue therapy for 1 to 2 weeks after symptom resolution, for a total therapy of 4 to 6 weeks.

≥60 kg: Oral: Initial: 2 mg/kg/day in divided doses twice daily for 2 days (maximum dose: Chorioretinitis: 25 mg/dose; severe or CNS disease: 50 mg/dose); followed by 1 mg/kg/day once daily (maximum dose: Chorioretinitis: 25 mg/dose; severe or CNS disease: 75 mg/dose). Continue therapy for 1 to 2 weeks after symptom resolution, for a total therapy of 4 to 6 weeks.

Toxoplasmosis, congenital infection (independent of HIV status); treatment: In combination with sulfadiazine and leucovorin:

Infants: Oral: Initial: 2 mg/kg/day once daily or in 2 divided doses for 2 days, then 1 mg/kg/day once daily for 2 to 6 months, then 1 mg/kg/dose 3 times weekly (eg, Monday, Wednesday, Friday); maximum dose: 25 mg/dose; total treatment duration: 12 months (AAP [Red Book 2018]; HHS [OI pediatric 2019]).

Toxoplasmosis, prophylaxis, in hematopoietic cell transplantation recipients (Tomblyn 2009):

Infants and Children: Oral: 1 mg/kg/day once daily with clindamycin and leucovorin; maximum dose: 75 mg/dose. Start after engraftment and administer as long as the patient remains on immunosuppressive therapy.

Adolescents: Oral: 25 to 75 mg once daily with clindamycin and leucovorin. Start after engraftment and administer as long as the patient remains on immunosuppressive therapy.

Toxoplasmosis, prophylaxis, in HIV-exposed/-infected patients:

Primary prophylaxis: Alternative therapy to sulfamethoxazole/trimethoprim:

Infants and Children (HHS [OI pediatric 2019]): Oral:

In combination with dapsone and oral leucovorin: 1 mg/kg/day once daily; maximum dose: 25 mg/dose.

In combination with atovaquone and oral leucovorin: Infants and Children 4 to 24 months: 1 mg/kg/day or 15 mg/m2/day once daily; maximum dose: 25 mg/dose.

Adolescents (HHS [OI adult 2019]): Oral:

In combination with dapsone and oral leucovorin: 50 mg or 75 mg once weekly.

In combination with atovaquone and oral leucovorin: 25 mg once daily.

Secondary prophylaxis/suppressive therapy:

Infants and Children: Oral: 1 mg/kg/day or 15 mg/m2/day once daily (maximum dose: 25 mg/dose) with leucovorin and sulfadiazine, clindamycin, or atovaquone (HHS [OI pediatric 2019]).

Adolescents (HHS [OI adult 2019]): Oral:

In combination with sulfadiazine or clindamycin: 25 to 50 mg once daily plus leucovorin.

In combination with atovaquone: 25 mg once daily plus leucovorin.

Extemporaneously Prepared

2 mg/mL oral suspension

A 2 mg/mL oral suspension may be made with tablets and a 1:1 mixture of Simple Syrup, NF and methylcellulose 1%. Crush forty 25 mg tablets in a mortar and reduce to a fine powder. Add small portions of vehicle and mix to a uniform paste; mix while adding vehicle in incremental proportions to almost 500 mL; transfer to a calibrated bottle, rinse mortar with vehicle, and add quantity of vehicle sufficient to make 500 mL. Label "shake well" and "refrigerate". Stable for 91 days.

Nahata MC, Pai VB, and Hipple TF, Pediatric Drug Formulations, 5th ed, Cincinnati, OH: Harvey Whitney Books Co, 2004.

Administration

Oral: Administer with meals to minimize GI distress.

Dietary Considerations

Take with meals.

Storage

Store at 15°C to 25°C (59°F to 77°F). Protect from light.

Drug Interactions

Antipsychotic Agents (Phenothiazines): Antimalarial Agents may increase the serum concentration of Antipsychotic Agents (Phenothiazines). Monitor therapy

Artemether: May enhance the adverse/toxic effect of Antimalarial Agents. Management: Artemether/Lumefantrine (combination product) should not be used with other antimalarials unless there is no other treatment option. Avoid combination

Dapsone (Systemic): May enhance the adverse/toxic effect of Antimalarial Agents. Specifically, concomitant use of dapsone with antimalarial agents may increase the risk for hemolytic reactions. Antimalarial Agents may enhance the adverse/toxic effect of Dapsone (Systemic). Specifically, concomitant use of antimalarial agents with dapsone may increase the risk of hemolytic reactions. Management: Closely monitor patients for signs/symptoms of hemolytic reactions with concomitant use of dapsone and antimalarial agents, particularly in patients deficient in glucose-6-phosphate dehydrogenase (G6PD), methemoglobin reductase, or with hemoglobin M. Consider therapy modification

Dapsone (Topical): Antimalarial Agents may enhance the adverse/toxic effect of Dapsone (Topical). Specifically, the risk of hemolytic reactions may be increased. Management: Closely monitor for signs/symptoms of hemolytic reactions with concomitant use of topical dapsone and antimalarial agents. Patients with glucose-6-phosphate dehydrogenase deficiency may be at particularly high risk for adverse hematologic effects. Consider therapy modification

Folic Acid: May diminish the therapeutic effect of Pyrimethamine. Management: Folic acid doses greater than 2.5 mg per day should be avoided due to the potential for sulfadoxine/pyrimethamine treatment failure. Consider limiting folic acid use to no more than 0.4 mg per day for women of child-bearing age. Consider therapy modification

LORazepam: May enhance the hepatotoxic effect of Pyrimethamine. Monitor therapy

Lumefantrine: Antimalarial Agents may enhance the adverse/toxic effect of Lumefantrine. Management: Artemether/Lumefantrine (combination product) should not be used with other antimalarials unless there is no other treatment option. Avoid combination

Methotrexate: Pyrimethamine may enhance the adverse/toxic effect of Methotrexate. Monitor therapy

Methylfolate: May diminish the therapeutic effect of Pyrimethamine. Monitor therapy

PEMEtrexed: Pyrimethamine may enhance the adverse/toxic effect of PEMEtrexed. Monitor therapy

PRALAtrexate: Pyrimethamine may enhance the adverse/toxic effect of PRALAtrexate. Monitor therapy

Proguanil: Pyrimethamine may enhance the adverse/toxic effect of Proguanil. Monitor therapy

Raltitrexed: Pyrimethamine may enhance the adverse/toxic effect of Raltitrexed. Monitor therapy

Sulfonamide Antibiotics: Pyrimethamine may enhance the adverse/toxic effect of Sulfonamide Antibiotics. Monitor therapy

Trimethoprim: Pyrimethamine may enhance the adverse/toxic effect of Trimethoprim. Monitor therapy

Adverse Reactions

Frequency not defined.

Cardiovascular: Cardiac arrhythmia (large doses)

Dermatologic: Erythema multiforme, skin rash, Stevens-Johnson syndrome, toxic epidermal necrolysis

Gastrointestinal: Anorexia, glossitis (atrophic), vomiting

Hematologic & oncologic: Leukopenia, megaloblastic anemia, pancytopenia, thrombocytopenia

Genitourinary: Hematuria

Hypersensitivity: Anaphylaxis

Respiratory: Eosinophilic pneumonitis

Warnings/Precautions

Concerns related to adverse effects:

• Hematologic: Megaloblastic anemia, leukopenia, thrombocytopenia, and pancytopenia have been reported; most commonly with high doses. Monitor CBC and platelets twice weekly in patients receiving high-dose therapy (eg, when used for toxoplasmosis treatment).

Disease-related concerns:

• Folate deficiency: Use caution in patients with possible folate deficiency (eg, malabsorption syndrome, alcoholism).

• G6PD deficiency: Use with caution in patients with possible G6PD deficiency.

• Hepatic impairment: Use with caution in patients with hepatic impairment.

• Renal impairment: Use with caution in patients with renal impairment.

• Seizure disorders: Use with caution in patients with a history of seizure disorders.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Other warnings/precautions:

• Leucovorin: Administer leucovorin to prevent hematologic complications due to pyrimethamine-induced folic acid deficiency state; continue leucovorin during therapy and for 1 week after therapy is discontinued (to account for long half-life of pyrimethamine) (HHS [OI pediatric 2019])

Monitoring Parameters

CBC, including platelet counts twice weekly with high-dose therapy (eg, when used for toxoplasmosis treatment; frequency not defined for lower doses); hepatic and renal function

Reproductive Considerations

Pregnancy should be avoided during therapy.

Pregnancy Risk Factor

C

Pregnancy Considerations

Pyrimethamine should be used with caution in patients with possible folate deficiency, including pregnant women. If administered during pregnancy (ie, for toxoplasmosis), supplementation of folate is strongly recommended.

Pyrimethamine is recommended for treatment of T. gondii in pregnant women living with HIV, including those with a strong suspicion of fetal infection. Pyrimethamine should not be used in the first trimester (HHS [OI adult 2019]).

Patient Education

What is this drug used for?

• It may be used to treat toxoplasmosis.

• It may be given to you for other reasons. Talk with the doctor.

Frequently reported side effects of this drug

• Vomiting

• Lack of appetite

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Chills

• Abnormal heartbeat

• Severe loss of strength and energy

• Seizures

• Blood in the urine

• Bruising

• Bleeding

• Sore throat

• Pale skin

• Pinpoint red spots on skin

• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.

Further information

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