Pyrimethamine

Name: Pyrimethamine

Pyrimethamine Brand Names

Pyrimethamine may be found in some form under the following brand names:

  • Daraprim

  • Fansidar

  • Rebalance

Pyrimethamine Overdose

If you take too much pyrimethamine, call your healthcare provider or local Poison Control Center, or seek emergency medical attention right away.

How should I take pyrimethamine?

Follow all directions on your prescription label. Your doctor may occasionally change your dose. Do not take this medicine in larger or smaller amounts or for longer than recommended.

Your dosage and the length of time you take pyrimethamine will depend on the reason you are taking this medicine. In some cases pyrimethamine is taken for several weeks, and you may need to take the medicine only once per week.

The pyrimethamine dose for treating toxoplasmosis is much higher than the dose for malaria.

Follow your doctor's dosing instructions very carefully.

Your dose may need to be cut in half after you have been taking pyrimethamine for 1 to 3 weeks (after 2 to 4 days for a child).

Take with food if pyrimethamine upsets your stomach or affects your appetite.

Pyrimethamine is often given in combination with other medications. Use all medications as directed by your doctor. Read the medication guide or patient instructions provided with each medication. Do not change your doses or medication schedule without your doctor's advice.

While using pyrimethamine, you may need frequent blood tests.

Store at room temperature away from moisture, heat, and light.

What happens if I miss a dose?

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

Pyrimethamine dosing information

Usual Adult Dose for Malaria Prophylaxis:

25 mg orally once a week. Prophylaxis should begin one week prior to departure and continue for at least 6 to 10 weeks following exposure.

Usual Adult Dose for Toxoplasmosis:

Initially: 50 to 75 mg orally once a day with 1 to 4 g of a sulfonamide (e.g., sulfadoxine, sulfadiazine). Continue for 1 to 3 weeks, depending on response and tolerance. Dosage for each drug may then be reduced by one-half and continued for an additional 4 or 5 weeks. Patients receiving pyrimethamine should also receive folinic acid.

Usual Adult Dose for Toxoplasmosis -- Prophylaxis:

1 mg/kg or 15 mg/m2 (max 25 mg) orally every day plus folinic acid (leucovorin) 5 mg orally every 3 days plus sulfadiazine 85 to 120 mg/kg/day divided into 2 to 4 oral doses. Clindamycin 20 to 30 mg/kg/day may be used in place of sulfadiazine as an alternative regimen.

Usual Adult Dose for Pneumocystis Pneumonia Prophylaxis:

50 to 75 mg orally once a week. Pyrimethamine is used in combination with dapsone and leucovorin. This is considered an alternative regimen for patients who do not tolerate trimethoprim-sulfamethoxazole.

Usual Pediatric Dose for Malaria Prophylaxis:

Less than 4 years: 6.25 mg orally once a week.

4 to 10 years: 12.5 mg orally once a week.

Usual Pediatric Dose for Toxoplasmosis:

Newborns and infants:
Initial: 2 mg/kg/day orally divided every 12 hours for 2 days, then 1 mg/kg/day once daily given with sulfadiazine for the first 6 months; next 6 months: 1 mg/kg/day 3 times per week with sulfadiazine; oral folinic acid 5 to 10 mg 3 times per week should be administered to prevent hematological toxicity.

1 to 12 years: 2 mg/kg/day divided every 12 hours for 3 days followed by 1 mg/kg/day (maximum 25 mg/day) once daily or divided twice daily for 4 weeks given with sulfadiazine; oral folinic acid 5 to 10 mg 3 times per week should be administered to prevent hematological toxicity.

Cautions for Pyrimethamine

Contraindications

  • Hypersensitivity to pyrimethamine or any ingredient in the formulation.167

  • Megaloblastic anemia caused by folate deficiency.167

Warnings/Precautions

Warnings

Hematologic Effects

High pyrimethamine dosage may cause folic acid deficiency and cause reversible bone marrow depression.125 167 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 dosage or discontinue if signs of folic or folinic acid deficiency occur.167 Perform CBCs twice weekly.167 (See Laboratory Monitoring under Cautions.)

Pyrimethamine dosage used for treatment of toxoplasmosis approaches the toxic level and is associated with adverse effects resulting from folic acid deficiency.167 Megaloblastic anemia, leukopenia, thrombocytopenia, and pancytopenia reported.125 167 When pyrimethamine is used for treatment of toxoplasmosis, give leucovorin (folinic acid) concomitantly.134 167 (See Toxoplasmosis under Pediatric Patients and also under Adults, in Dosage and Administration.)

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

Hypersensitivity reactions, including severe reactions such as erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, and anaphylaxis, reported with pyrimethamine, especially when used with a sulfonamide.167

Severe, sometimes fatal, hypersensitivity reactions have occurred in patients receiving fixed-combination preparation of sulfadoxine and pyrimethamine (sulfadoxine/pyrimethamine; Fansidar).110 111 112 114 128 132 136 139 140 143 144 145 159 In most reported cases, fatalities resulted from severe cutaneous reactions, including erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis.110 139 140 143 144 145 159 Pulmonary hypersensitivity reactions,111 138 140 fatal reaction involving the skin, liver, and kidneys,112 and fatal hepatitis also reported.132 The fixed-combination preparation no longer commercially available in US,168 but may still be available in other countries.161

Discontinue pyrimethamine at first sign of rash, sore throat, fever, arthralgia, cough, shortness of breath, pallor, jaundice, or glossitis.167

General Precautions

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, and seizures reported with high pyrimethamine dosage.125 Headache, light-headedness, insomnia, depression, malaise, fatigue, and irritability also reported rarely.125

In patients with seizure disorders being treated for toxoplasmosis, use low initial pyrimethamine dosage to avoid potential nervous system toxicity.167

Laboratory Monitoring

Monitor CBC, including platelet counts, twice weekly in patients receiving high pyrimethamine dosage.167

Specific Populations

Pregnancy

Category C.167

Manufacturer states use during pregnancy only when potential benefits outweigh possible risks;167 if pyrimethamine is used to treat toxoplasmosis during pregnancy, administer leucovorin concurrently to decrease hematologic toxicity.167

CDC, NIH, and IDSA state that, although pyrimethamine has been associated with birth defects in animals, human data have not suggested an increased risk for defects and the drug can be administered to pregnant women after first trimester.155 These experts state that recommended treatment of T. gondii encephalitis in pregnant women, including use of pyrimethamine, should be the same as that for nonpregnant adults.155

Warn women of childbearing potential to avoid becoming pregnant while receiving the drug.167

Lactation

Pyrimethamine distributed into milk.147 167 Discontinue nursing or the drug, taking into account the importance of the drug to the woman.167

Pediatric Use

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

Keep out of the reach of children.167

Geriatric Use

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

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

Common Adverse Effects

Hypersensitivity reactions, GI effects, myelosuppression.167

Interactions for Pyrimethamine

Specific Drugs

Drug

Interaction

Comments

Dapsone

Additive adverse hematologic effects; increased risk of agranulocytosis180

No clinically important effect on pyrimethamine pharmacokinetics125

Monitor for adverse hematologic effects more frequently than usual180

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

Pyrimethamine and sulfonamides interfere with folic acid synthesis in susceptible organisms; possible synergism between the drugs used to therapeutic advantage in treatment of toxoplasmosis125 168 and has been used to therapeutic advantage in prevention or treatment of malaria134 167 168 188 189

Increased risk of bone marrow suppression if used with other folic acid antagonists167

Pyrimethamine used in conjunction with sulfadiazine for treatment of toxoplasmosis134 155 156 184 185

Pyrimethamine has been used in conjunction with sulfadoxine for prevention or treatment of malaria, but no longer recommended for such use143

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

Lorazepam

Mild hepatotoxicity reported when pyrimethamine and lorazepam used concomitantly167

Methotrexate

May increase risk of bone marrow suppression167

Use with caution167

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

Phenytoin

Decreased 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

Zidovudine

May increase risk of bone marrow suppression167

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

What do I need to tell my doctor BEFORE I take Pyrimethamine?

  • If you have an allergy to pyrimethamine or any other part of pyrimethamine.
  • If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.
  • If you have anemia caused by low folic acid stores.
  • If you are breast-feeding or plan to breast-feed.

This is not a list of all drugs or health problems that interact with this medicine.

Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take pyrimethamine with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.

Off Label Uses

Congenital toxoplasmosis

Based on the US Department of Health and Human Services (HHS) guidelines for the prevention and treatment of opportunistic infections in pediatric patients, for the treatment of congenital toxoplasmosis, pyrimethamine (in combination with sulfadiazine and leucovorin calcium) is effective and recommended.

Isosporiasis (Isospora belli infection) in HIV-infected patients (adolescents and adults)

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 adolescent and adult HIV-infected patients.

Pneumocystis pneumonia (PCP) in HIV-infected patients (adolescents and adults)

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 adolescent and adult HIV-infected patients.

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

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 adolescent and adult HIV-infected patients.

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

Based on the US Department of Health and Human Services (HHS) Guidelines for Prevention and Treatment of Opportunistic Infections Among HIV-Exposed and HIV-Infected Children, pyrimethamine in combination with leucovorin and other agents is an effective and recommended agent in the treatment of, primary prophylaxis of, or as chronic maintenance (secondary prophylaxis) of Toxoplasma gondii encephalitis in HIV-exposed or -infected children.

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 Hepatic Impairment

There are no dosage adjustments provided in the manufacturer’s labeling. Use with caution.

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

Bosentan: CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Bosentan. Management: Concomitant use of both a CYP2C9 inhibitor and a CYP3A inhibitor or a single agent that inhibits both enzymes with bosentan is likely to cause a large increase in serum concentrations of bosentan and is not recommended. See monograph for details. Monitor therapy

Cannabis: CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Cannabis. More specifically, tetrahydrocannabinol serum concentrations may be increased. Monitor therapy

Carvedilol: CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Carvedilol. Specifically, concentrations of the S-carvedilol enantiomer may be increased. Monitor therapy

CYP2C9 Substrates: CYP2C9 Inhibitors (Moderate) may decrease the metabolism of CYP2C9 Substrates. Monitor therapy

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

Dronabinol: CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Dronabinol. 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

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

Tetrahydrocannabinol: CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Tetrahydrocannabinol. Monitor therapy

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.

Side Effects

Consult your pharmacist.

In the US -

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088 or at www.fda.gov/medwatch.

In Canada - Call your doctor for medical advice about side effects. You may report side effects to Health Canada at 1-866-234-2345.

List Pyrimethamine Powder side effects by likelihood and severity.

For the Consumer

Applies to pyrimethamine: oral tablet

Along with its needed effects, pyrimethamine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking pyrimethamine:

Less common
  • Black, tarry stools
  • blood in urine or stools
  • cough or hoarseness
  • fever or chills
  • irritation or soreness of tongue
  • lower back or side pain
  • painful or difficult urination
  • pinpoint red spots on skin
  • unusual bleeding or bruising
Rare
  • Bleeding or crusting sores on lips
  • chest pain or discomfort
  • muscle cramps or pain
  • redness, blistering, peeling, or loosening of skin
  • skin rash
  • sores, ulcers, and/or white spots in mouth
  • sore throat
  • unusual tiredness or weakness
Frequency not known
  • Blood in urine
  • diarrhea
  • difficulty swallowing
  • dizziness
  • fainting spells
  • fast, slow, or irregular heartbeat
  • hives
  • itching
  • joint or muscle pain
  • lightheadedness
  • pale skin
  • pounding or rapid pulse
  • puffiness or swelling of the eyelids or around the eyes, face, lips or tongue
  • rapid breathing
  • red, irritated eyes
  • red skin lesions, often with a purple center
  • shortness of breath
  • swollen glands
  • tightness in chest
  • unexplained bleeding or bruising
  • wheezing
Symptoms of overdose
  • Abdominal or stomach pain
  • convulsions (seizures)
  • increased excitability
  • vomiting (severe and continuing)

Some side effects of pyrimethamine may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

Less common
  • Diarrhea
  • loss of appetite
  • nausea
  • vomiting

For Healthcare Professionals

Applies to pyrimethamine: compounding powder, oral tablet

Gastrointestinal

Gastrointestinal side effects have included nausea, vomiting, diarrhea, glossitis, and atrophic glossitis, particularly with high doses. Gastrointestinal intolerance may be minimized by administering pyrimethamine with food.[Ref]

Hypersensitivity

Hypersensitivity reactions have been reported when pyrimethamine is administered with a sulfonamide. These reactions may be severe and include erythema multiforme, Stevens-Johnson Syndrome, toxic epidermal necrolysis, Lyell's syndrome, hepatitis, anaphylaxis, and pulmonary reactions. Fatal reactions have been estimated to occur in one of 11,000 to 25,000 patients treated. Hypersensitivity reactions have also been reported with pyrimethamine/clindamycin combinations and are usually limited to maculopapular rashes.[Ref]

Hematologic

Hematologic side effects have occurred, especially when large doses of pyrimethamine are administered. Thrombocytopenia, megaloblastic anemia, leukopenia, pancytopenia, agranulocytosis, and fatalities have been reported.[Ref]

Nervous system

Nervous system toxicity is problematic with higher dosages of pyrimethamine. Ataxia, tremors, and seizures may occur.[Ref]

Respiratory

Respiratory side effects have rarely included pulmonary eosinophilia.[Ref]

Cardiovascular

Cardiovascular side effects have included arrhythmias, particularly with high doses.[Ref]

Metabolic

Metabolic side effects have included hyperphenylalaninemia, particularly when pyrimethamine is given in combination with a sulfonamide.[Ref]

Oncologic

Oncologic side effects have included two reports of malignancy; both were associated with pyrimethamine treatment for toxoplasmosis: 1 patient developed chronic granulocytic leukemia after 2 years of therapy and 1 patient developed reticulum cell sarcoma after 14 months of therapy. Animal studies have revealed increased lung tumors with intraperitoneal administration.[Ref]

Some side effects of pyrimethamine may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

(web3)