Pyrimethamine (Daraprim) is a folate inhibitor and primarily used as an antiparasitic drug. It is used to treat patients with toxoplasmosis and other parasitic infections.

Pyrimethamine Uses:

• Toxoplasmosis:
  • It is indicated in the treatment of toxoplasmosis (in combination with a sulfonamide).
• Off Label Use of Pyrimethamine in Adults:
• It is used in HIV infected persons in the following conditions
  • Isospora belli infection (isosporiasis) in HIV-infected patients
  • Pneumocystis pneumonia (PCP) in HIV infected patients
  • Toxoplasma gondii encephalitis (For treatment/primary prophylaxis/chronic maintenance therapy) in HIV-infected patients

Pyrimethamine (Daraprim) Dose in Adults

Pyrimethamine (Daraprim) Dose in the treatment of Isosporiasis ( Isospora belli infection) in HIV-infected patients (alternative agent) (off-label): Oral:

• Treatment:
  • 50 - 75 mg once a day with leucovorin calcium
• Chronic maintenance (secondary prophylaxis):
  • 25 mg once a day with leucovorin calcium

Pyrimethamine (Daraprim) Dose in the treatment of Pneumocystis pneumonia (PCP) in HIV-infected patients (alternative agent): Oral:

• Primary prophylaxis:
  • 50 - 75 mg once a week with dapsone and leucovorin calcium or
  •  25 mg once a day with atovaquone and leucovorin calcium
• Chronic maintenance (secondary prophylaxis):
  • 50 - 75 mg once a week with dapsone and leucovorin calcium or
  • 25 mg once a day combined atovaquone and leucovorin calcium

Pyrimethamine (Daraprim) Dose in the treatment of Toxoplasmosis:

• Oral: 50 - 75 mg per day for 1 - 3 weeks then the dose can be reduced by 50% and continue for 4 - 5 weeks
• In combination with sulfonamide and leucovorin calcium.

Pyrimethamine (Daraprim) Dose in the treatment of Toxoplasmosis in HIV-infected patients (off-label): Oral:

• Primary prophylaxis (alternative agent):
  • 50 or 75 mg once a week with dapsone and leucovorin calcium or
  • 25 mg once a day with atovaquone and leucovorin calcium
• Chronic maintenance therapy (secondary prophylaxis):
  • 25 - 50 mg once a day with sulfadiazine and leucovorin calcium or
  • 25 - 50 mg once a day with clindamycin and leucovorin calcium or
  • 25 mg once a day with atovaquone and leucovorin calcium (alternative regimen)

Pyrimethamine (Daraprim) Dose in the treatment of Toxoplasma gondii encephalitis:

• 200 mg as a single dose, followed by Weight based dose of 50 mg (<60 kg) or 75 mg (≥60 kg) daily, with sulfadiazine and leucovorin calcium for at least 6 weeks or
•  200 mg as a single dose, followed by a weight-based dose of 50 mg (<60 kg) or 75 mg (≥60 kg) daily, with leucovorin calcium plus clindamycin or atovaquone or azithromycin (alternative regimens).

Note:

• 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, if pyrimethamine is not available readily and there is a delay in procuring for suspected or documented toxoplasmosis who have no history of sulfa allergy, trimethoprim-sulfamethoxazole should be used in place of pyrimethamine-containing regimens until pyrimethamine is available.

Pyrimethamine (Daraprim) Dose in  Childrens  

Pyrimethamine (Daraprim) Dose in the treatment of Isosporiasis (Isospora belli), HIV-exposed/-positive:

• Treatment:
  • Infants and Children: Oral: 1 mg/kg once a day with leucovorin for 14 days; (maximum daily dose: 75 mg/day)
  • Adolescents: Oral: 50 - 75 mg once a day with leucovorin
• Chronic maintenance:
  • Infants and Children: Oral: 1 mg/kg once a day with leucovorin (maximum daily dose: 25 mg/day)
  • Adolescents: Oral: 25 mg once a day with leucovorin

Pyrimethamine (Daraprim) Dose in the treatment of Toxoplasmosis:

• Treatment:
  • Congenital toxoplasmosis (independent of HIV status): Oral:
    • Infants:
      • Initial: 2 mg/kg/dose once a day for 2 days followed by
      • 1 mg/kg/day once a day with sulfadiazine for 2 - 6 months then
      • 1 mg/kg/day 3 times/week (eg, MWF) with sulfadiazine
      • To reduce chances of hematological toxicity oral leucovorin should be given throughout the course (total treatment duration: 12 months)
  • Acquired infection:
    • HIV-exposed/-positive:
      • Infants and Children: Oral
        • 2 mg/kg (maximum dose: 50 mg/dose) once a day for 3 days followed by 1 mg/kg (maximum dose: 25 mg) once a day
        • combined with sulfadiazine or clindamycin and leucovorin
        • continue for at least 6 weeks; if clinically or radiologically extensive disease or response is not adequate, longer duration should be given
      • Adolescents: Oral
        • Encephalitis: 200 mg once as a single dose followed by daily doses as follows
        • Daily weight-based doses: For weight <60 kg: 50 mg or for weight ≥60 kg: 75 mg once a day
        • Typically used in combination with sulfadiazine and leucovorin; other combination regimens include clindamycin, atovaquone, or azithromycin and leucovorin
        • Continue for at least 6 weeks; If clinically or radiologically extensive disease or response is not adequate, longer duration should be given
    • Non-HIV-exposed/-positive:

Note: Use in combination with sulfadiazine or clindamycin and leucovorin. Leucovorin should be used to prevent hematologic toxicity. Continue until 1 - 2 weeks after the symptoms resolved.

• Children: Oral: 2 mg/kg (maximum dose: 50 mg/dose) once a day for 2 days , followed by 1 mg/kg/day (maximum dose: 25 mg/dose) once a day for 3 - 6 weeks
• Adolescents: Oral: 200 mg once as a single dose; then 50 - 75 mg once a day for 3 - 6 weeks
• Prophylaxis:
  • The first episode of Toxoplasma gondii:
    • HIV-exposed/-positive:
      • Infants and Children: Oral:
        • 1 mg/kg/day once a day with dapsone plus oral leucovorin (Maximum dose: 25mg/dose)
        • Infants and Children 4 - 24 months: 1 mg/kg or 15 mg/m once a day with atovaquone plus oral leucovorin (Maximum dose: 25 mg/dose)
      • Adolescents: Oral:
        • 50 mg or 75 mg once a week with leucovorin and dapsone
        • 25 mg once a day with leucovorin and atovaquone
  • Hematopoietic cell transplantation recipients:
    • Infants and Children:
      • Oral: 1 mg/kg/day of pyrimethamine once a day with clindamycin and leucovorin
      • Start after engraftment and continue as long as the patient is on immunosuppressive therapy.
    • Adolescents:
      • Oral: 25 - 75 mg once a day with clindamycin and leucovorin
      • Start after engraftment and continue as long as the patient is 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 a day with oral leucovorin and sulfadiazine, clindamycin, or atovaquone
        • Maximum dose: 25 mg
      • Adolescents: Oral:
        • 25 - 50 mg once a day with leucovorin, sulfadiazine, or clindamycin
        • 25 mg once a day with leucovorin and atovaquone

Pyrimethamine (Daraprim) Dose in the treatment of Malaria:

Note: There is a prevalence of Pyrimethamine resistance worldwide. And CDC does not recommend malaria prophylaxis or treatment. However, the World Health Organization (WHO) guidelines still include pyrimethamine in prophylaxis and treatment of malaria.

• Chemoprophylaxis: Begin prophylaxis before entering the endemic area:
  • Infants and Children <4 years: Oral: 6.25 mg once a week
  • Children 4 to 10 years: Oral: 12.5 mg once a week
  • Children >10 years and Adolescents: Oral: 25 mg once a week
• Treatment (non-falciparum malaria; use in conjunction with a sulfonamide [eg, sulfadoxine]):
  • Children 4 to 10 years: Oral: 25 mg a day for 2 days
    • Administer once a week chemoprophylaxis regimen (after clinical cure) for ≥10 weeks
  • Children >10 years and Adolescents:
    • Oral: 25 mg a day for 2 days
    • Administer once a week chemoprophylaxis regimen (following clinical cure) for ≥10 weeks
    • Note: Do not use Pyrimethamine monotherapy; If it needs to be given as monotherapy, give 50 mg a day for 2 days; then (following clinical cure) give once a week chemoprophylaxis regimen for ≥10 weeks.

Pyrimethamine (Daraprim) Dose in the Pneumocystis jirovecii pneumonia (PCP) (HIV-exposed/-positive);

Primary prophylaxis or chronic maintenance (secondary prophylaxis):

• Adolescents: Oral:
  • 50 - 75 mg once a week with dapsone and leucovorin
  • 25 mg once a day with atovaquone and leucovorin

Pregnancy Risk Factor C

• Studies on animal reproduction have shown adverse effects.
• Folate supplementation is highly recommended if pyrimethamine is required to be administered during pregnancy.
• Avoid pregnancy while on therapy.

Use of pyrimetamine while breastfeeding

• Breast milk contains pyrimethamine, which can cause significant (or even greater) levels of pyrimethamine to be secreted by infants who are breastfed.
• It is worth considering the combination of sulfonamide (or dapsone) and pyrimethamine (a combination that is often used).

Dose in Kidney disease:

No dose adjustments listed in the manufacturer’s labeling. Use with caution.   

Dose in Liver disease:

No dose adjustments listed in the manufacturer’s labeling. Use with caution.   

Pyrimethamine (Daraprim) Side effects:

• 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

Contraindications to Pyrimethamine (Daraprim):

• Hypersensitivity
• Megaloblastic anemia due to folate deficiency

Warnings and precautions

• Hematologic:
  • Pancytopenia, anemia (megaloblastic), thrombocytopenia and leukopenia have all been reported. Usually, these were with high doses.
  • Patients receiving high-dose therapy should be monitored twice weekly by the CBC
• Folate deficiency:
  • Use caution if the patient has a folate deficiency such as malabsorption syndrome, pregnancy or alcoholism.
• G6PD deficiency:
  • Patients with G6PD deficiency should be cautious when using this product.
• Hepatic impairment
  • It is best to avoid it if you have a hepatic impairment.
• Renal impairment
  • It is best to avoid it if you have renal impairment.
• Seizure disorders:
  • Patients with seizure disorders history should be cautious.

Pyrimethamine: Drug Interaction

Note: Drug Interaction Categories:

• Risk Factor C: Monitor When Using Combination
• Risk Factor D: Consider Treatment Modification
• Risk Factor X: Avoid Concomitant Use

Monitoring parameters:

• CBC, twice weekly with high-dose therapy
• Hepatic function
• Renal function

How to administer Pyrimethamine (Daraprim)?

Oral: Administer with meals (to minimize gastrointestinal discomfort)   

Mechanism of action of Pyrimethamine (Daraprim):

• Pyrimethamine inhibits dihydrofolate reductase enzyme in parasites, resulting in inhibition of vital tetrahydrofolic acid synthesis. 
• It inhibits the dihydrofolate reductase enzyme found in parasites.
• This results in inhibition of vital Tetrahydrofolic Acid synthesis.

Absorption:

• Well absorbed

Distribution:

• Distribution to organs like the kidneys, liver, lung, and spleen

Protein binding:

• 87%

Half-life elimination

• 80-95 hours

Time to reach peak

• Serum: 2-6 hours

Excretion:

• Urine (16%-32%)

International Brand Names of Pyrimethamine (Daraprim):

• Daraprim
• Daraprin
• Malocide
• Malomin
• Meta
• Primet
• Pyrison
• Tindurin
• Toxopirin

Pyrimethamine Brand Names in Pakistan: