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Pronunciation
(peer i METH a meen)
Generic Available (U.S.)
No
Brand Names: U.S.
Brand Names: Canada
Pharmacologic Category
Pharmacologic Category Synonyms
Use: Labeled Indications
Prophylaxis of malaria due to susceptible strains of plasmodia; used in conjunction with a sulfonamide for the treatment of uncomplicated malaria due to susceptible strains of plasmodia (alternative agent; not preferred therapy); synergistic combination with sulfonamide in treatment of toxoplasmosis
Pregnancy Risk Factor
C
Pregnancy Considerations
Teratogenic effects 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.
Lactation
Enters breast milk/not recommended (AAP rates “compatible”; AAP 2001 update pending)
Breast-Feeding Considerations
Pyrimethamine enters breast milk and may result in significant systemic concentrations in breast-fed infants. The effect of concurrent therapy with sulfonamide or dapsone (frequently used with pyrimethamine as combination treatment) must be considered.
Contraindications
Hypersensitivity to pyrimethamine or any component of the formulation; megaloblastic anemia secondary to folate deficiency
Warnings/Precautions
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:
• Leucovorin: When used for more than 3-4 days, it may be advisable to administer leucovorin calcium to prevent hematologic complications.
Other warnings/precautions:
• Monitoring: Monitor CBC and platelet counts every 2 weeks.
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
Metabolism/Transport Effects
Inhibits CYP2C9 (moderate)
Drug Interactions
Antipsychotic Agents (Phenothiazines): Antimalarial Agents may increase the serum concentration of Antipsychotic Agents (Phenothiazines). Risk C: 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. Risk X: Avoid combination
Carvedilol: CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Carvedilol. Specifically, concentrations of the S-carvedilol enantiomer may be increased. Risk C: Monitor therapy
CYP2C9 Substrates: CYP2C9 Inhibitors (Moderate) may decrease the metabolism of CYP2C9 Substrates. Risk C: Monitor therapy
Dapsone: May enhance the adverse/toxic effect of Antimalarial Agents. More specifically, dapsone may increase the risk for hemolytic reactions. Antimalarial Agents may enhance the adverse/toxic effect of Dapsone. More specifically, 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. Risk D: Consider therapy modification
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. Risk D: 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. Risk D: Consider therapy modification
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. Risk X: Avoid combination
Methylfolate: May diminish the therapeutic effect of Pyrimethamine. Risk C: Monitor therapy
Storage
Store at 15°C to 25°C (59°F to 77°F). Protect from light.
Mechanism of Action
Inhibits parasitic dihydrofolate reductase, resulting in inhibition of vital tetrahydrofolic acid synthesis
Pharmacodynamics/Kinetics
Onset of action: ~1 hour
Absorption: Well absorbed
Distribution: Widely, mainly in blood cells, kidneys, lungs, liver, and spleen; crosses into CSF
Protein binding: 80% to 87%
Metabolism: Hepatic
Half-life elimination: 80-95 hours
Time to peak, serum: 1.5-8 hours
Excretion: Urine (20% to 30% as unchanged drug)
Dosage
Oral:
Isosporiasis (
Isospora belli
infection) in HIV-positive patients (unlabeled use; CDC, 2009): Adults:
Treatment (alternative to trimethoprim-sulfamethoxazole): 50-75 mg once daily in combination with leucovorin calcium
Chronic maintenance (secondary prophylaxis): 25 mg once daily in combination with leucovorin calcium
Malaria chemoprophylaxis: Begin prophylaxis before entering endemic area: Note: Current CDC recommendations for malaria prophylaxis do not include the use of pyrimethamine; resistance to pyrimethamine is prevalent worldwide.
Manufacturer's labeling:
Children <4 years: 6.25 mg once weekly
Children 4-10 years: 12.5 mg once weekly
Children >10 years and Adults: 25 mg once weekly
Malaria treatment (non-
falciparum
malaria; use in conjunction with a sulfonamide [eg, sulfadoxine]): Note: Current CDC recommendations for the malaria treatment do not include the use of pyrimethamine; resistance to pyrimethamine is prevalent worldwide.
Manufacturer's labeling:
Children 4-10 years: 25 mg daily for 2 days; following clinical cure, administer a once weekly chemoprophylaxis regimen for ≥10 weeks
Children >10 years and Adults: 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 (children receive 25 mg daily for 2 days), then (following clinical cure) administer a once-weekly chemoprophylaxis regimen for ≥10 weeks.
Pneumocystis jirovecii
pneumonia (PCP) in HIV-positive patients (unlabeled use; CDC, 2009): Adults:
Prophylaxis (alternative to trimethoprim-sulfamethoxazole): 50 mg once weekly in combination with dapsone and leucovorin calcium; or 25 mg once daily with atovaquone in combination with oral leucovorin calcium
Chronic maintenance (secondary prophylaxis; alternative to trimethoprim-sulfamethoxazole): 50-75 mg once weekly in combination with dapsone and leucovorin calcium; or 25 mg once daily with atovaquone in combination with leucovorin calcium
Toxoplasmosis treatment: Manufacturer's labeling:
Children: Loading dose: 1 mg/kg/day divided into 2 equal daily doses for 2-4 days, then may decrease dose to 0.5 mg/kg/day divided into 2 doses for 4 weeks; use with a sulfonamide in combination with leucovorin calcium
Adults: 50-75 mg/day for 1-3 weeks depending on patient's tolerance and response, then may reduce dose by 50% and continue for 4-5 weeks; use with a sulfonamide in combination with leucovorin calcium
Toxoplasmosis prophylaxis and treatment in HIV-positive patients (unlabeled; CDC, 2009):
Prophylaxis for first episode of Toxoplasma gondii:
Children ≥1 month of age: 1 mg/kg/day (or 15 mg/m2) once daily (maximum: 25 mg), with dapsone or atovaquone in combination with leucovorin calcium
Adolescents and Adults (alternative to trimethoprim sulfamethoxazole): 50 mg or 75 mg once weekly with dapsone in combination with leucovorin calcium; or 25 mg once daily with atovaquone in combination with leucovorin calcium
Prophylaxis to prevent recurrence of Toxoplasma gondii:
Children ≥1 month of age: 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
Adolescents and Adults: 25-50 mg once daily with sulfadiazine in combination with leucovorin calcium (preferred); or 25-50 mg once daily with clindamycin in combination with leucovorin calcium; or 25 mg once daily with atovaquone in combination with leucovorin calcium
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 2-6 months, followed by 1 mg/kg administered 3 times weekly, with sulfadiazine or clindamycin in combination with leucovorin calcium (treatment duration: 12 months)
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 (treatment duration: ≥6 weeks)
Treatment of Toxoplasma gondii encephalitis: Adolescents and Adults: 200 mg as a single dose, followed by 50 mg (<60 kg) or 75 mg (≥60 kg) daily, with sulfadiazine in combination with 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, with clindamycin, atovaquone, or azithromycin in combination with leucovorin calcium
Administration: Oral
Administer with meals to minimize GI distress.
Monitoring Parameters
CBC, including platelet counts
Dietary Considerations
Take with meals to minimize GI distress.
Patient Education
Take with meals. Tablets may be crushed to prepare oral suspensions of the drug in water, cherry syrup, or sucrose-containing solutions at a concentration of 1 mg drug/mL of liquid. Regular blood tests will be necessary during therapy. If used for prophylaxis, consult with prescriber in order to begin 2 weeks before traveling to endemic areas, continue during travel period, and for 6-10 weeks following return. May cause GI distress, loss of appetite, dizziness, lightheadedness, insomnia, changes in mentation, changes in skin pigmentation, or rash. Report persistent GI disturbance (nausea, vomiting, diarrhea, cramping), chest pain or palpitation, unusual fatigue, easy bruising, bleeding, or bloody emesis.
Dental Health: Effects on Dental Treatment
Key adverse event(s) related to dental treatment: Xerostomia (normal salivary flow resumes upon discontinuation). Atrophic glossitis has been reported.
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
No information available to require special precautions
Mental Health: Effects on Mental Status
May rarely cause drowsiness, insomnia, or depression
Mental Health: Effects on Psychiatric Treatment
May cause leukopenia; use caution with clozapine and carbamazepine; mild hepatotoxicity associated with concurrent usage of lorazepam
Nursing: Physical Assessment/Monitoring
Evaluate any patient history of renal or hepatic impairment or seizures prior to beginning therapy. When used for more than 3-4 days, it may be advisable to give leucovorin calcium to prevent hematologic complications. Monitor for arrhythmias, rash, GI disturbance, hematuria, and megoblastic anemia periodically during therapy.
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, oral:
Daraprim®: 25 mg [scored]
Pricing: U.S. (www.drugstore.com)
Tablets (Daraprim)
25 mg (30): $260.00
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.
References
American Academy of Pediatrics Committee on Drugs, "Transfer of Drugs and Other Chemicals Into Human Milk," Pediatrics, 2001, 108(3):776-89.
Akinyanju O, Goddell JC, and Ahmed I, “Pyrimethamine Poisoning,” Br Med J, 1973, 4(885):147-8.
Centers for Disease Control and Prevention, “Guidelines for the Prevention and Treatment of Opportunistic Infections Among HIV-Exposed and HIV-Infected Children: Recommendations from CDC, the National Institutes of Health, the HIV Medicine Association of the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the American Academy of Pediatrics,” MMWR Recomm Rep, 2009, 58(RR-11):1-166. Available at http://aidsinfo.nih.gov/contentfiles/Pediatric_OI.pdf
Centers for Disease Control and Prevention, “Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents: Recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America,” MMWR Recomm Rep, 2009, 58(RR-4):1-207.
Chute JP, Decker CF, and Cotelingam J, “Severe Megaloblastic Anemia Complicating Pyrimethamine Therapy,” Ann Intern Med, 1995, 122(11):884-5.
“Drugs for Parasitic Infections,” Med Lett Drugs Ther, 2002. Available at http://www.medicalletter.com/freedocs/parasitic.pdf
Katlama C, De Wit S, O'Doherty E, et al, “Pyrimethamine-Clindamycin vs Pyrimethamine-Sulfadiazine as Acute and Long-Term Therapy for Toxoplasmic Encephalitis in Patients With AIDS,” Clin Infect Dis, 1996, 22(2):268-75.
Phillips-Howard PA and West LJ, “Serious Adverse Drug Reactions to Pyrimethamine-Sulfadoxine, Pyrimethamine-Dapsone, and to Amodiaquine in Britain,” J R Soc Med, 1990, 83(2):82-5.
Porter SB and Sande MA, “Toxoplasmosis of the Central Nervous System in the Acquired Immunodeficiency Syndrome,” N Engl J Med, 1992, 327(23):1643-8.
Torre D, Casari S, Speranza F, et al, “Randomized Trial of Trimethoprim-Sulfamethoxazole Versus Pyrimethamine-Sulfadiazine for Therapy of Toxoplasmic Encephalitis in Patients With AIDS. Italian Collaborative Study Group,” Antimicrob Agents Chemother, 1998, 42(6):1346-9.
Van Voorhis WC, “Therapy and Prophylaxis of Systemic Protozoan Infections,” Drugs, 1990, 40(2):176-202.
White NJ, “Clinical Pharmacokinetics of Antimalarial Drugs,” Clin Pharmacokinet, 1985, 10(3):187-215.
World Health Organization, “Guidelines for the Treatment of Malaria,” 2010, World Health Organization, Geneva. Available at http://whqlibdoc.who.int/publications/2010/9789241547925_eng.pdf
International Brand Names
Lexi-Comp.com
Last full review/revision February 2012
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