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Pyrimethamine

Medically reviewed by Drugs.com. Last updated on Mar 2, 2019.

Pronunciation

(peer i METH a meen)

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Tablet, Oral:

Daraprim: 25 mg [DSC]

Daraprim: 25 mg [scored]

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

Isosporiasis (Isospora belli infection) in HIV-infected patients

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

Pneumocystis pneumonia (PCP) in HIV-infected patients

Based on the US Department of Health and Human Services (HHS) Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents, 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 (PCP) in HIV-infected patients.

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

Based on the US Department of Health and Human Services (HHS) Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents, 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 HIV-infected patients.

Contraindications

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

Dosing: Adult

Isosporiasis (Isospora belli infection) in HIV-infected patients (alternative agent) (off-label use) (HHS [OI adult 2015]): 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 (PCP) in HIV-infected patients (alternative agent) (off-label use) (HHS [OI adult 2017]): 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

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 HIV-infected patients (off-label) (HHS [OI adult 2017]): 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

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 or azithromycin (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 the HIV-infected adults and adolescents, 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

Isosporiasis (Isospora belli), HIV-exposed/-positive:

Treatment:

Infants and Children: Oral: 1 mg/kg once daily in combination with leucovorin for 14 days; maximum daily dose: 75 mg/day (DHHS [pediatric], 2013)

Adolescents: Oral: 50 to 75 mg once daily in combination with leucovorin (DHHS [adult], 2013)

Chronic maintenance:

Infants and Children: Oral: 1 mg/kg once daily in combination with leucovorin; maximum daily dose: 25 mg/day (DHHS [pediatric], 2013)

Adolescents: Oral: 25 mg once daily in combination with leucovorin (DHHS [adult], 2013)

Toxoplasmosis:

Treatment:

Congenital toxoplasmosis (independent of HIV status): Oral: Infants: Initial: 2 mg/kg/dose once daily for 2 days, then 1 mg/kg/day once daily given with sulfadiazine for 2 to 6 months; then 1 mg/kg/day 3 times/week (eg, MWF) with sulfadiazine; oral leucovorin should be administered throughout entire course to prevent hematologic toxicity (total treatment duration: 12 months) (DHHS [pediatric], 2013; McAuley, 2008)

Acquired infection:

HIV-exposed/-positive:

Infants and Children: Oral: 2 mg/kg (maximum dose: 50 mg/dose) once daily for 3 days followed by 1 mg/kg (maximum dose: 25 mg) once daily in combination with sulfadiazine or clindamycin and leucovorin; continue for at least 6 weeks; consider longer duration if clinical or radiologic disease is extensive or incomplete response; follow with chronic suppressive therapy (DHHS [pediatric], 2013)

Adolescents: Oral: Encephalitis: 200 mg once as a single dose, followed by weight-based daily dosing: For weight <60 kg: 50 mg or for weight ≥60 kg: 75 mg once daily, typically used in combination with sulfadiazine and leucovorin; other combination regimens include clindamycin, atovaquone, or azithromycin and leucovorin; continue for at least 6 weeks; consider longer duration if clinical or radiologic disease is extensive or incomplete response (DHHS [adult], 2013)

Non-HIV-exposed/-positive (Red Book [AAP, 2012]): Note: Use in combination with sulfadiazine or clindamycin; oral leucovorin should be administered to prevent hematologic toxicity. Continue therapy until 1 to 2 weeks after the resolution of symptoms.

Children: Oral: 2 mg/kg (maximum dose: 50 mg/dose) once daily for 2 days, followed by 1 mg/kg/day (maximum dose: 25 mg/dose) once daily for 3 to 6 weeks

Adolescents: Oral: 200 mg once as a single dose; then 50 to 75 mg once daily for 3 to 6 weeks

Prophylaxis:

First episode of Toxoplasma gondii:

HIV-exposed/-positive:

Infants and Children (DHHS [pediatric], 2013): Oral:

In combination with dapsone: 1 mg/kg/day once daily (maximum dose: 25 mg/dose) with dapsone plus oral leucovorin

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

Adolescents (DHHS [adult], 2013): Oral:

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

In combination with atovaquone: 25 mg once daily plus leucovorin

Hematopoietic cell transplantation recipients (Tomblyn, 2009):

Infants and Children: Oral: 1 mg/kg/day of pyrimethamine once daily (maximum single dose: 75 mg) with clindamycin and leucovorin. 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.

Recurrence of Toxoplasma gondii (secondary prophylaxis; suppressive therapy): HIV-exposed/-positive:

Infants and Children: Oral: 1 mg/kg or 15 mg/m2 once daily (maximum dose: 25 mg) with sulfadiazine, clindamycin, or atovaquone, plus oral leucovorin (DHHS [pediatric], 2013)

Adolescents (DHHS [adult], 2013): Oral:

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

In combination with atovaquone: 25 mg once daily plus leucovorin

Malaria: Note: Current CDC recommendations for malaria prophylaxis or treatment do not include the use of pyrimethamine; resistance to pyrimethamine is prevalent worldwide. (CDC, 2013); however, pyrimethamine is still discussed in the World Health Organization (WHO) treatment guidelines (WHO, 2010; WHO, 2011).

Chemoprophylaxis: Begin prophylaxis before entering endemic area:

Infants and Children <4 years: Oral: 6.25 mg once weekly

Children 4 to 10 years: Oral: 12.5 mg once weekly

Children >10 years and Adolescents: Oral: 25 mg once weekly

Treatment (non-falciparum malaria; use in conjunction with a sulfonamide [eg, sulfadoxine]):

Children 4 to 10 years: Oral: 25 mg daily for 2 days; following clinical cure, administer a once-weekly chemoprophylaxis regimen for ≥10 weeks. Note: Pyrimethamine monotherapy is generally not recommended.

Children >10 years and Adolescents: Oral: 25 mg daily for 2 days; following clinical cure, administer a once-weekly chemoprophylaxis regimen for ≥10 weeks. Note: Pyrimethamine monotherapy is not recommended; if circumstances arise where it must be used alone in semi-immune patients, give 50 mg daily for 2 days; then (following clinical cure) administer a once-weekly chemoprophylaxis regimen for ≥10 weeks.

Pneumocystis jirovecii pneumonia (PCP) (HIV-exposed/-positive); primary prophylaxis or chronic maintenance (secondary prophylaxis) (DHHS [adult], 2013): Adolescents: Oral:

In combination with dapsone and leucovorin: 50 to 75 mg once weekly with dapsone and leucovorin

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

Extemporaneously Prepared

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): 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. 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. 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, pregnancy, 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, 2013)

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

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse events have been observed in animal reproduction studies. If administered during pregnancy (ie, for toxoplasmosis), supplementation of folate is strongly recommended. Pregnancy should be avoided during therapy.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience vomiting or lack of appetite. Have patient report immediately to prescriber chills, abnormal heartbeat, severe loss of strength and energy, seizures, hematuria, bruising, bleeding, pharyngitis, pale skin, or pinpoint red spots on skin (HCAHPS).

• Educate patient about signs of a significant reaction (eg, 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. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

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