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Pyrimethamine

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]

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

Malaria chemoprophylaxis: Chemoprophylaxis of malaria due to susceptible strains of plasmodia.

Limitations of use: Resistance to pyrimethamine is prevalent worldwide; it is not suitable as a prophylactic agent for travelers to most areas.

Malaria treatment: Treatment (in combination with a sulfonamide) of acute malaria due to susceptible strains of plasmodia.

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

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 (off-label use; HHS [OI adult 2015]): Oral:

Treatment (alternative to trimethoprim-sulfamethoxazole): 50 to 75 mg once daily in combination with leucovorin calcium

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

Malaria chemoprophylaxis: Oral: 25 mg once weekly. Note: Current CDC recommendations for malaria prophylaxis do not include the use of pyrimethamine (CDC 2014); resistance to pyrimethamine is prevalent worldwide.

Malaria treatment (non-falciparum malaria; use in conjunction with a sulfonamide [eg, sulfadoxine]): Oral: 25 mg daily for 2 days; following clinical cure, administer a once-weekly chemoprophylaxis regimen for ≥10 weeks. Note: Pyrimethamine use alone is not recommended; if circumstances arise where it must be used alone in semi-immune patients, give adults 50 mg daily for 2 days; then (following clinical cure) administer a once-weekly chemoprophylaxis regimen for ≥10 weeks

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

Pneumocystis pneumonia (PCP) in HIV-infected patients (off-label use; HHS [OI adult 2015]): Oral:

Primary prophylaxis (alternative to trimethoprim-sulfamethoxazole): 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; alternative to trimethoprim-sulfamethoxazole): 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 2015]): Oral:

Primary prophylaxis (alternative to trimethoprim sulfamethoxazole): 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 (HHS [OI adult 2015])

Chronic maintenance therapy (secondary prophylaxis): 25 to 50 mg once daily in combination with sulfadiazine and leucovorin calcium (preferred); or 25 to 50 mg once daily in combination with clindamycin and leucovorin calcium; or 25 mg once daily in combination with atovaquone and leucovorin calcium (HHS [OI adult 2015])

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 (preferred); 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. 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 (HHS [OI adult, 2015]).

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Isosporiasis (Isospora belli infection) in HIV-infected patients (off-label use): Adolescents: Refer to adult dosing.

Malaria chemoprophylaxis: Oral: Begin prophylaxis before entering endemic area: Note: Current CDC recommendations for malaria prophylaxis do not include the use of pyrimethamine (CDC 2014); resistance to pyrimethamine is prevalent worldwide.

Infants and Children <4 years: 6.25 mg once weekly

Children 4 to 10 years: 12.5 mg once weekly

Children >10 years and Adolescents: Refer to adult dosing.

Malaria treatment (non-falciparum malaria; use in conjunction with a sulfonamide [eg, sulfadoxine]): Oral: Note: Current CDC recommendations for malaria treatment do not include the use of pyrimethamine (CDC 2013); resistance to pyrimethamine is prevalent worldwide.

Children ≥4 years and Adolescents: 25 mg daily for 2 days; following clinical cure, administer a once weekly chemoprophylaxis regimen for ≥10 weeks

Note: Pyrimethamine use alone is not recommended; if circumstances arise where it must be used alone in semi-immune patients, give children >10 years and adolescents 50 mg daily for 2 days (children 4 to 10 years of age receive 25 mg daily for 2 days), then (following clinical cure) administer a once-weekly chemoprophylaxis regimen for ≥10 weeks

Pneumocystis pneumonia (PCP) in HIV-infected patients (off-label use): Adolescents: Refer to adult dosing.

Toxoplasmosis treatment: Oral: Loading dose: 1 mg/kg/day divided into 2 equal daily doses for 2 to 4 days, then may decrease dose to 0.5 mg/kg/day divided into 2 doses for 4 weeks; use with a sulfonamide and leucovorin calcium

Toxoplasmosis in HIV-infected patients (off-label): Oral:

Primary prophylaxis:

Infants and Children: 1 mg/kg/day (or 15 mg/m2) once daily (maximum: 25 mg), with dapsone or atovaquone, in combination with leucovorin calcium (HHS [OI pediatric 2013])

Adolescents: Refer to adult dosing.

Chronic maintenance therapy (secondary prophylaxis):

Infants and Children: 1 mg/kg/day (or 15 mg/m2) once daily (maximum: 25 mg) given with sulfadiazine (or atovaquone or clindamycin), in combination with leucovorin calcium (HHS [OI pediatric 2013])

Adolescents: Refer to adult dosing.

Treatment of congenital toxoplasmosis: Infants and Children: Loading dose: 2 mg/kg/day once daily for 2 days, then 1 mg/kg/day once daily for 2 to 6 months, followed by 1 mg/kg administered 3 times weekly, in combination with leucovorin calcium and sulfadiazine or clindamycin (treatment duration: 12 months) (HHS [OI pediatric 2013])

Treatment of acquired toxoplasmosis: Infants and Children: Acute induction: Loading dose: 2 mg/kg once daily (maximum: 50 mg/day) for 3 days, then 1 mg/kg/day once daily (maximum: 25 mg/day), with sulfadiazine or clindamycin in combination with leucovorin calcium. Continue acute induction therapy for ≥6 weeks, then follow with chronic suppressive therapy (HHS [OI pediatric 2013]).

Treatment of Toxoplasma gondii encephalitis: Adolescents: Refer to adult dosing.

Dosing: Renal Impairment

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

Dosing: Hepatic Impairment

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

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

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): 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

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

Adverse Reactions

Frequency not defined.

Cardiovascular: Arrhythmias (large doses)

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

Gastrointestinal: Anorexia, atrophic glossitis, vomiting

Hematologic: Leukopenia, megaloblastic anemia, pancytopenia, pulmonary eosinophilia, thrombocytopenia

Genitourinary: Hematuria

Miscellaneous: Anaphylaxis

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); liver 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, arrhythmia, 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.

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