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PYRIMETHAMINE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Pyrimethamine is a folic acid antagonist with antimicrobial activity.

Specific Substances

    1) 5-(4-Chlorophenyl)-6-ethylpyrimidine-2,4-diyldiamine
    2) BW 50-63
    3) Pirimetamin
    4) Pirimetamina
    5) Pirimetaminas
    6) Pirymetamina
    7) Pyrimetamiini
    8) Pyrimetamin
    9) Pyrimethamin
    10) Pyrimethaminum
    11) RP 4753
    12) CAS 58-14-0
    1.2.1) MOLECULAR FORMULA
    1) C12-H13-Cl-N4 (Prod Info DARAPRIM(R) oral tablets, 2003)

Available Forms Sources

    A) FORMS
    1) Pyrimethamine is available in the US as 25 mg tablets (Prod Info Daraprim(R), 2003). Pyrimethamine 25 mg is also available in combination with sulfadoxine 500 mg (Prod Info Fansidar(R), , 2004). Please refer to "SULFONAMIDE" management for further information on sulfadoxine.
    B) USES
    1) Pyrimethamine (Daraprim(R)) in combination with other antibiotics has been used for the treatment of toxoplasmosis and for the prophylaxis and treatment of malaria (Prod Info Daraprim(R), 2003).
    2) Pyrimethamine/sulfadoxine combination (Fansidar(R)) has been used for the prophylaxis and treatment of malaria (Prod Info Fansidar(R), , 2004).
    3) Please refer to "SULFONAMIDE" management for further information on sulfadoxine.

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Pyrimethamine is used for the treatment of toxoplasmosis and for the prophylaxis and treatment of malaria. It is usually used in combination with a sulfonamide (eg, sulfadoxine, sulfadiazine). Please refer to "SULFONAMIDES" management for further information on sulfonamide toxicity.
    B) PHARMACOLOGY: Pyrimethamine is a folic acid antagonist which binds to and reversibly inhibits the protozoal enzyme dihydrofolate reductase, selectively blocking conversion of dihydrofolic acid to its functional form, tetrahydrofolic acid. This depletes folate, an essential cofactor in the biosynthesis of nucleic acids, resulting in interference with protozoal nucleic acid and protein production. Protozoal dihydrofolate reductase is many times more tightly bound by pyrimethamine than the corresponding mammalian enzyme.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) The following adverse effects have been reported following therapeutic use of pyrimethamine: Nausea, vomiting, megaloblastic anemia, leukopenia, thrombocytopenia, pancytopenia, atrophic glossitis, hematuria, dysrhythmias, and pulmonary eosinophilia. SEVERE: Infrequently reported, but potentially serious effects such as Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, and anaphylaxis have been reported with pyrimethamine/sulfadoxine combination. Some cases have resulted in fatalities.
    E) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Abdominal pain, nausea, vomiting, skin hyperpigmentation, pruritus, diarrhea, fever, abdominal pain, cough, sore throat, irritability, myalgia, arthralgia, hyperbilirubinemia, elevated serum transaminases, and oral ulcers have been reported.
    2) SEVERE TOXICITY: Serious CNS effects can develop within 30 minutes to 2 hours of exposure. Loss of consciousness and seizures have been reported with pyrimethamine in young infants (1 to 2 years) within 2 hours of overdose. Generalized and prolonged seizures after pyrimethamine overdose may be followed by respiratory depression and circulatory collapse, and death within a few hours. Following chronic overdose, bone marrow depression may occur, manifested by neutropenia, thrombocytopenia, and macrocytic/megaloblastic anemia. Hemorrhagic effects have also been reported.
    0.2.20) REPRODUCTIVE
    A) Pyrimethamine and the combination sulfadoxine and pyrimethamine are classified as FDA pregnancy category C. In a parallel-group, open-label, individually randomized controlled superiority trial, limb anomalies were found in a small group of infants in Mali exposed over the second and third trimesters of pregnancy to either 2 or 3 doses of combination pyrimethamine/sulfadoxine for malaria prevention. Pyrimethamine was teratogenic in animal studies.
    0.2.21) CARCINOGENICITY
    A) Prolonged pyrimethamine use was associated with two cases of cancer (granulocytic leukemia and reticulum cell sarcoma) in humans.

Laboratory Monitoring

    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor vital signs, hepatic enzymes and renal function after significant overdose.
    C) Monitor serum electrolytes in patients with severe vomiting.
    D) Monitor serial CBC with differential and platelet count in symptomatic patients. Daily monitoring of CBC is recommended for several weeks after pyrimethamine overdose due to its long half-life.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Treat seizures with IV benzodiazepines; barbiturates or propofol may be needed if seizures persist or recur. Myelosuppression has been reported. Monitor serial CBC with differential and platelet count. For severe neutropenia, administer colony stimulating factor (eg; filgrastim, sargramostim). Transfusions as needed for severe thrombocytopenia, bleeding. In patients with acute allergic reaction, oxygen therapy, bronchodilators, diphenhydramine, corticosteroids, vasopressors and epinephrine may be required.
    C) DECONTAMINATION
    1) PREHOSPITAL: Prehospital gastrointestinal decontamination is generally not recommended because of the potential for CNS depression or persistent seizures and subsequent aspiration.
    2) HOSPITAL: Consider activated charcoal if the overdose is recent, the patient is not vomiting, and is able to maintain airway.
    D) AIRWAY MANAGEMENT
    1) Ensure adequate ventilation and perform endotracheal intubation early in patients with life-threatening cardiac dysrhythmias, significant CNS depression or severe allergic reactions.
    E) FOLIC ACID
    1) Administer folic acid or leucovorin/folinic acid at 5 to 15 mg orally daily to minimize hematologic toxicity. Should be started within 2 hours of overdose if possible.
    F) MYELOSUPPRESSION
    1) Monitor CBC with differential and platelet count. Continue monitoring CBC for several weeks due to pyrimethamine's long half-life. For severe neutropenia, administer colony stimulating factor. Filgrastim 5 mcg/kg/day subQ or IV over 15 to 30 minutes. Sargramostim 250 mcg/meter(2)/day IV over 4 hours. Transfusion of platelets and/or packed red cells may be needed in patients with severe thrombocytopenia, anemia or hemorrhage.
    G) ENHANCED ELIMINATION PROCEDURE
    1) Hemodialysis is UNLIKELY to be of value because of the high degree of protein binding of pyrimethamine.
    H) PATIENT DISPOSITION
    1) HOME CRITERIA: A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
    2) OBSERVATION CRITERIA: Patients with a deliberate overdose, and those who are symptomatic, need to be monitored for several hours. Neurologic symptoms usually occur rapidly (within 30 minutes to 2 hours) following ingestion. Patients that remain asymptomatic can be discharged. However, due to the long-half-life of pyrimethamine (96 hours), daily monitoring of peripheral blood counts is recommend for a few weeks after exposure until all hematologic parameters are normal.
    3) ADMISSION CRITERIA: Patients should be admitted for severe vomiting, electrolyte abnormalities, persistent cardiac dysrhythmias, mental status changes, myelosuppression, seizures, and respiratory failure. Patients should remain admitted until they are clearly improving and clinically stable.
    4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    I) PITFALLS
    1) When managing a suspected pyrimethamine overdose, the possibility of multidrug involvement should be considered. Symptoms of overdose are similar to reported side effects of the medication. Early symptoms of overdose may be delayed or not evident (ie, particularly myelosuppression), so reliable follow-up is imperative.
    J) PHARMACOKINETICS
    1) Well absorbed. Tmax: 2 to 6 hours. Elimination is slow. Plasma half-life: about 96 hours. Protein binding: 87%.
    K) DIFFERENTIAL DIAGNOSIS
    1) Includes other agents that may cause myelosuppression, seizures, or CNS depression (eg, toxic alcohols, benzodiazepines, opiates/opioids, antipsychotic medications).

Range Of Toxicity

    A) TOXICITY: Ingestion of 300 mg or more can produce toxicity, including gastrointestinal effects (eg; abdominal pain, nausea, severe vomiting). In severe cases, this may be followed by excitability, generalized and prolonged seizures, respiratory depression, circulatory collapse and death. PEDIATRIC: Fatalities have occurred in young children less than 2 years old following doses of 375 to 1625 mg. NEWBORN: A 7-day-old newborn was prescribed sulfadiazine 100 mg/kg/day in 3 divided doses (instead of 1 mg/kg/day), pyrimethamine 100 mg/kg/day in 3 divided doses, and folinic acid 50 mg/week in 2 divided doses. The pyrimethamine dosing error was discovered 3 days later after the patient received 4 doses of pyrimethamine. He developed moderate cholestasis, loss of appetite, vomiting, and seizures. Following supportive care, he recovered and was discharged a week after hospitalization.
    B) THERAPEUTIC DOSE: ADULT: Varies by indication; 25 to 75 mg/day orally. PEDIATRIC: Varies by indication; TOXOPLASMOSIS: 1 mg/kg/day orally in 2 equal daily doses; may be reduced after 2 to 4 days to half of the initial dose for about a month. ACUTE MALARIA: Monotherapy in semi-immune patients aged 4 to 10 years: 25 mg/day orally for 2 days. MALARIA CHEMOPROPHYLAXIS: Infants and children under age 4 years: 6.25 mg (one-fourth tablet) orally once weekly for at least 10 weeks. Children aged 4 to 10 years: 12.5 mg (one-half tablet) orally once weekly for at least 10 weeks. Children aged 10 years and older: 25 mg (one tablet) orally once weekly for at least 10 weeks.

Clinical Effects

Summary Of Exposure

    A) USES: Pyrimethamine is used for the treatment of toxoplasmosis and for the prophylaxis and treatment of malaria. It is usually used in combination with a sulfonamide (eg, sulfadoxine, sulfadiazine). Please refer to "SULFONAMIDES" management for further information on sulfonamide toxicity.
    B) PHARMACOLOGY: Pyrimethamine is a folic acid antagonist which binds to and reversibly inhibits the protozoal enzyme dihydrofolate reductase, selectively blocking conversion of dihydrofolic acid to its functional form, tetrahydrofolic acid. This depletes folate, an essential cofactor in the biosynthesis of nucleic acids, resulting in interference with protozoal nucleic acid and protein production. Protozoal dihydrofolate reductase is many times more tightly bound by pyrimethamine than the corresponding mammalian enzyme.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) The following adverse effects have been reported following therapeutic use of pyrimethamine: Nausea, vomiting, megaloblastic anemia, leukopenia, thrombocytopenia, pancytopenia, atrophic glossitis, hematuria, dysrhythmias, and pulmonary eosinophilia. SEVERE: Infrequently reported, but potentially serious effects such as Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, and anaphylaxis have been reported with pyrimethamine/sulfadoxine combination. Some cases have resulted in fatalities.
    E) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Abdominal pain, nausea, vomiting, skin hyperpigmentation, pruritus, diarrhea, fever, abdominal pain, cough, sore throat, irritability, myalgia, arthralgia, hyperbilirubinemia, elevated serum transaminases, and oral ulcers have been reported.
    2) SEVERE TOXICITY: Serious CNS effects can develop within 30 minutes to 2 hours of exposure. Loss of consciousness and seizures have been reported with pyrimethamine in young infants (1 to 2 years) within 2 hours of overdose. Generalized and prolonged seizures after pyrimethamine overdose may be followed by respiratory depression and circulatory collapse, and death within a few hours. Following chronic overdose, bone marrow depression may occur, manifested by neutropenia, thrombocytopenia, and macrocytic/megaloblastic anemia. Hemorrhagic effects have also been reported.

Vital Signs

    3.3.3) TEMPERATURE
    A) WITH POISONING/EXPOSURE
    1) FEVER: Hyperpyrexia (40.6 degrees C) has been reported with pyrimethamine in young infants (1 to 2 years) within 2 hours of overdose (Guignard, 1965; Akinyanju et al, 1973).
    2) CASE SERIES: During an outbreak of pyrimethamine toxicity in Pakistan, fever developed in 60 (51.3%) of the 664 patients with ischemic heart disease who received isosorbide mononitrate contaminated with about 50 mg of pyrimethamine (Khan Assir et al, 2014).

Heent

    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) PYRIMETHAMINE/SULFADOXINE combination has been reported to cause toxic amblyopia and iritis (Phillips-Howard & West, 1990).
    B) WITH POISONING/EXPOSURE
    1) CASE REPORT: Temporary blindness was reported in a 14-month-old following acute pyrimethamine overdose (450 mg) (Akinyanju et al, 1973).
    3.4.4) EARS
    A) WITH POISONING/EXPOSURE
    1) CASE REPORT: Temporary deafness was reported in a 14-month-old following acute pyrimethamine overdose (450 mg) (Akinyanju et al, 1973).
    3.4.6) THROAT
    A) WITH POISONING/EXPOSURE
    1) SORE THROAT: CASE SERIES: During an outbreak of pyrimethamine toxicity in Pakistan, sore throat developed in 37 (31.6%) of the 664 patients with ischemic heart disease who received isosorbide mononitrate contaminated with about 50 mg of pyrimethamine (Khan Assir et al, 2014).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) TACHYCARDIA
    1) WITH POISONING/EXPOSURE
    a) Tachycardia has been reported with pyrimethamine (450 mg) in young infants (1 to 2 years) within 2 hours of overdose (Guignard, 1965; Akinyanju et al, 1973).
    B) ELECTROCARDIOGRAM ABNORMAL
    1) WITH THERAPEUTIC USE
    a) Cardiac rhythm disturbances (type unspecified) may occur in patients receiving higher doses used for toxoplasmosis (Prod Info DARAPRIM(R) oral scored tablets, 2013).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) DISORDER OF RESPIRATORY SYSTEM
    1) WITH THERAPEUTIC USE
    a) Pulmonary eosinophilia has been reported rarely in patients using pyrimethamine (Prod Info DARAPRIM(R) oral scored tablets, 2013).
    b) PYRIMETHAMINE/SULFADOXINE: A non-fatal case of progressive pulmonary infiltrates and eosinophilia after prophylaxis with pyrimethamine/sulfadoxine combination was reported (Svanbom et al, 1984). However, it is unclear from the data presented if pyrimethamine/sulfadoxine combination was the actual cause of pulmonary alveolar infiltrates in this patient.
    c) PYRIMETHAMINE/DAPSONE: Pulmonary eosinophilia was described in 3 patients after receiving pyrimethamine/dapsone (Maloprim(R)) for 3 to 5 weeks for malaria prophylaxis. In a fourth patient, pulmonary eosinophilia was described after 3 weeks of prophylaxis with Daraclor(R) pyrimethamine/chloroquine. All patients improved after withdrawal of malaria prophylaxis; 2 patients required antibiotics and steroid therapy. Self-rechallenge with Maloprim(R) in one patient resulted in cardiorespiratory arrest. It is speculated that the pyrimethamine component was the causal agent of pulmonary toxicity in these patients (Davidson et al, 1988).
    d) PYRIMETHAMINE/SULFADOXINE: Hypersensitivity pneumonitis occurred in a 64-year-old male after approximately one month of pyrimethamine/sulfadoxine combination therapy. The patient developed an influenza-like illness after approximately 1 month of pyrimethamine/sulfadoxine combination administration; pyrimethamine/sulfadoxine combination was initiated 2 weeks prior to departure from Canada, and continued for two weeks in Kenya and then several days in England, where the patient developed an influenza-like illness. Four days later, the patient travelled to Switzerland, where he presented with symptoms of pneumonia. The patient deteriorated rapidly, developing respiratory failure and requiring mechanical ventilation for 4 weeks. Recovery occurred slowly with steroid therapy (McCormack & Morgan, 1987).
    2) WITH POISONING/EXPOSURE
    a) Tachypnea and apnea have been reported with pyrimethamine in young infants (1 to 2 years) within 2 hours of overdose (Guignard, 1965; Akinyanju et al, 1973).
    b) CASE SERIES: During an outbreak of pyrimethamine toxicity in Pakistan, cough developed in 49 (41.9%) of the 664 patients with ischemic heart disease who received isosorbide mononitrate contaminated with about 50 mg of pyrimethamine. One patient developed dyspnea (Khan Assir et al, 2014).
    B) BRONCHOSPASM
    1) WITH THERAPEUTIC USE
    a) PYRIMETHAMINE/SULFADOXINE combination has been reported to cause bronchospasm (Phillips-Howard & West, 1990).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) SEIZURE
    1) WITH POISONING/EXPOSURE
    a) Loss of consciousness and seizures have been reported with pyrimethamine in young infants (1 to 2 years) within 2 hours of overdose (Guignard, 1965; Akinyanju et al, 1973).
    b) Generalized and prolonged seizures after pyrimethamine overdose may be followed by respiratory depression and circulatory collapse, and death within a few hours (Prod Info DARAPRIM(R) oral scored tablets, 2013).
    c) CASE REPORT: An 8-month-old infant who was inadvertently given 50 mg tablets instead of the 5 mg prescribed, developed a seizure on the second day and 2 further seizures on the 8th day after resuming therapy, despite having therapeutic phenobarbital levels (Cheron et al, 1987).
    d) CASE REPORT: A 7-month-old infant developed loss of consciousness and generalized seizures after receiving 30 mg of pyrimethamine instead of the 3 mg prescribed (10 times the usual dose) over 10 days for congenital toxoplasmosis. During the previous week, she experienced irritability and vomiting. Following treatment with diazepam (intrarectal, then 3 mg/day), she recovered completely and was discharged on hospital day 7 (Tracqui et al, 1993).
    e) PYRIMETHAMINE/SULFADIAZINE: A 7-day-old newborn with asymptomatic congenital toxoplasmosis was prescribed sulfadiazine 100 mg/kg/day in 3 divided doses, pyrimethamine 100 mg/kg/day in 3 divided doses (instead of 1 mg/kg/day), and folinic acid 50 mg/week in 2 divided doses. The pyrimethamine dosing error was discovered 3 days later after the patient received 4 doses of pyrimethamine. Laboratory results revealed isolated, moderate cholestasis (total bilirubin = 74 mcmol/L; conjugated bilirubin 40 mcmol/L). At this time, pyrimethamine and sulfadiazine were discontinued and folinic acid dose was increased to 25 mg/day. About 48 hours after receiving the first overdose, he developed partial seizures which resolved after receiving 1 dose of phenobarbital. He also had loss of appetite and vomiting that resolved 5 days later. The cholestasis resolved spontaneously and he was discharged after 1 week of hospitalization. The antiparasitic treatment was restarted and on 3-month followup, the child was doing well and tolerated the treatment (Genuini et al, 2011).
    B) LOSS OF CONSCIOUSNESS
    1) WITH POISONING/EXPOSURE
    a) Loss of consciousness and seizures have been reported with pyrimethamine in young infants (1 to 2 years) within 2 hours of overdose (Guignard, 1965; Akinyanju et al, 1973).
    b) CASE REPORT: A 7-month-old infant developed loss of consciousness and generalized seizures after receiving 30 mg of pyrimethamine instead of the 3 mg prescribed (10 times the usual dose) over 10 days for congenital toxoplasmosis. During the previous week, she experienced irritability and vomiting. Following treatment with diazepam (intrarectal, then 3 mg/day), she recovered completely and was discharged on hospital day 7 (Tracqui et al, 1993).
    C) HEADACHE
    1) WITH POISONING/EXPOSURE
    a) PYRIMETHAMINE/SULFADOXINE: Moderate headache was reported by four family members who mistakenly took a chronic overdose of pyrimethamine 25 mg/sulfadoxine 500 mg combination, 1 tablet daily for 19 days (Lindberg et al, 1986).
    D) FEELING IRRITABLE
    1) WITH POISONING/EXPOSURE
    a) CASE SERIES: During an outbreak of pyrimethamine toxicity in Pakistan, irritability developed in 33 (28.2%) of the 664 patients with ischemic heart disease who received isosorbide mononitrate contaminated with about 50 mg of pyrimethamine (Khan Assir et al, 2014).
    E) DYSESTHESIA
    1) WITH POISONING/EXPOSURE
    a) CASE SERIES: During an outbreak of pyrimethamine toxicity in Pakistan, one patient developed a new onset dysesthesia of their hands and feet (Khan Assir et al, 2014).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) GASTROINTESTINAL TRACT FINDING
    1) WITH THERAPEUTIC USE
    a) Anorexia, vomiting, and atrophic glossitis may occur with pyrimethamine treatment. These symptoms usually disappears following the reduction of dosage (Prod Info DARAPRIM(R) oral scored tablets, 2013).
    2) WITH POISONING/EXPOSURE
    a) CASE SERIES: During an outbreak of pyrimethamine toxicity in Pakistan, diarrhea developed in 62 (53%) of the 664 patients with ischemic heart disease who received isosorbide mononitrate contaminated with about 50 mg of pyrimethamine. Abdominal pain and oral ulcers developed in 57 (48.7%) and 5 (4.2%) of the patients, respectively. One patient developed constipation and hiccups (Khan Assir et al, 2014).
    b) CASE REPORT: A 7-month-old infant developed irritability, vomiting, loss of consciousness and generalized seizures after receiving 30 mg of pyrimethamine instead of the 3 mg prescribed (10 times the usual dose) over 10 days for congenital toxoplasmosis. Following treatment with diazepam (intrarectal, then 3 mg/day), she recovered completely and was discharged on hospital day 7 (Tracqui et al, 1993).
    c) PYRIMETHAMINE/SULFADIAZINE: A 7-day-old newborn with asymptomatic congenital toxoplasmosis was prescribed sulfadiazine 100 mg/kg/day in 3 divided doses, pyrimethamine 100 mg/kg/day in 3 divided doses (instead of 1 mg/kg/day), and folinic acid 50 mg/week in 2 divided doses. The pyrimethamine dosing error was discovered 3 days later after the patient received 4 doses of pyrimethamine. Laboratory results revealed isolated, moderate cholestasis (total bilirubin = 74 mcmol/L; conjugated bilirubin 40 mcmol/L). At this time, pyrimethamine and sulfadiazine were discontinued and folinic acid dose was increased to 25 mg/day. About 48 hours after receiving the first overdose, he developed partial seizures which resolved after receiving 1 dose of phenobarbital. He also had loss of appetite and vomiting that resolved 5 days later. The cholestasis resolved spontaneously and he was discharged after 1 week of hospitalization. The antiparasitic treatment was restarted and on 3-month followup, the child was doing well and tolerated the treatment (Genuini et al, 2011).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) JAUNDICE
    1) WITH POISONING/EXPOSURE
    a) PYRIMETHAMINE/SULFADOXINE: Mild elevation of liver enzymes was reported in one case following a chronic overdose of pyrimethamine 25 mg/sulfadoxine 500 mg one tablet daily for 19 days (Lindberg et al, 1986).
    B) GRANULOMATOUS HEPATITIS
    1) WITH THERAPEUTIC USE
    a) PYRIMETHAMINE/SULFADOXINE: Noncaseating hepatic granulomas were described in two elderly patients (75 and 69 years of age) following pyrimethamine/sulfadoxine combination therapy for malaria prophylaxis. Both cases were documented by liver biopsy (Lazar et al, 1985). These two cases were reported during a 13-month period. Another case of granulomatous hepatitis, also confirmed by liver biopsy, has been reported (Murphy & Phair, 1986).
    C) INFLAMMATORY DISEASE OF LIVER
    1) WITH THERAPEUTIC USE
    a) PYRIMETHAMINE/SULFADOXINE: Hepatitis was described in 7 patients receiving pyrimethamine/sulfadoxine combination prophylaxis for malaria. Recurrence was described in a patient given pyrimethamine/sulfadoxine combination again 3 years after the first exposure. The duration of therapy ranged from 14 to 104 days before the appearance of icterus (mean, 74 days). However, it is unclear from the data presented if pyrimethamine/sulfadoxine combination was the actual cause of the hepatitis in these patients (Wejstal et al, 1986).
    D) HEPATIC NECROSIS
    1) WITH THERAPEUTIC USE
    a) PYRIMETHAMINE/SULFADOXINE: A fatal case of multisystemic toxicity was reported in a 60-year-old female, presumably due to pyrimethamine/sulfadoxine combination. Two weeks after beginning antimalarial prophylaxis with pyrimethamine/sulfadoxine combination plus chloroquine, the patient developed fever, diarrhea, and vomiting. Upon continuing her prophylactic regimen, the patient developed jaundice and elevated serum levels of bilirubin, alkaline phosphatase, and alanine aminotransferase. Liver biopsy indicated extensive focal hepatic necrosis. The patient expired 4 weeks after the onset of illness. Extensive diagnostic studies, before and after death, failed to find an etiology for her illness and pyrimethamine/sulfadoxine combination was presumed to be the likely cause (Selby et al, 1985).
    b) PYRIMETHAMINE/SULFADOXINE: Fatal hepatic necrosis was described in a 15-year-old girl following 4 doses of pyrimethamine/sulfadoxine combination 500 mg weekly (with chloroquine) as antimalarial prophylaxis. The patient took 2 doses prior to departure for Ecuador, developed fever, fatigue, and sore throat approximately 2 days after taking the third dose while in Ecuador; the fourth dose was taken after 2 weeks in Ecuador, followed in 1 week by the occurrence of fever, nausea, and sore throat, and subsequently skin rash and darkening of the urine. The patient subsequently died of fulminant hepatic failure and E coli sepsis. Autopsy revealed massive hepatic necrosis with marked ductular proliferation and diffuse hypertrophy of Kupffer cells. It is suggested that immediate withdrawal of pyrimethamine/sulfadoxine combination be undertaken in any patient developing hepatic function abnormalities (Zitelli et al, 1987).
    E) CHOLESTASIS
    1) WITH POISONING/EXPOSURE
    a) PYRIMETHAMINE/SULFADIAZINE: A 7-day-old newborn with asymptomatic congenital toxoplasmosis was prescribed sulfadiazine 100 mg/kg/day in 3 divided doses, pyrimethamine 100 mg/kg/day in 3 divided doses (instead of 1 mg/kg/day), and folinic acid 50 mg/week in 2 divided doses. The pyrimethamine dosing error was discovered 3 days later after the patient received 4 doses of pyrimethamine. Laboratory results revealed isolated, moderate cholestasis (total bilirubin = 74 mcmol/L; conjugated bilirubin 40 mcmol/L). At this time, pyrimethamine and sulfadiazine were discontinued and folinic acid dose was increased to 25 mg/day. About 48 hours after receiving the first overdose, he developed partial seizures which resolved after receiving 1 dose of phenobarbital. He also had loss of appetite and vomiting that resolved 5 days later. The cholestasis resolved spontaneously and he was discharged after 1 week of hospitalization. The antiparasitic treatment was restarted and on 3-month followup, the child was doing well and tolerated the treatment (Genuini et al, 2011).
    F) HYPERBILIRUBINEMIA
    1) WITH POISONING/EXPOSURE
    a) CASE SERIES: During an outbreak of pyrimethamine toxicity in Pakistan, hyperbilirubinemia and elevated serum transaminases developed in 6 of the 664 patients with ischemic heart disease who received isosorbide mononitrate contaminated with about 50 mg of pyrimethamine. Four of the 6 patients died (Khan Assir et al, 2014).
    G) INCREASED LIVER ENZYMES
    1) WITH POISONING/EXPOSURE
    a) CASE SERIES: During an outbreak of pyrimethamine toxicity in Pakistan, hyperbilirubinemia and elevated serum transaminases developed in 6 of the 664 patients with ischemic heart disease who received isosorbide mononitrate contaminated with about 50 mg of pyrimethamine. Four of the 6 patients died (Khan Assir et al, 2014).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) ACUTE RENAL FAILURE SYNDROME
    1) WITH THERAPEUTIC USE
    a) PYRIMETHAMINE/SULFADOXINE: A fatal case of multisystemic toxicity, including acute oliguric renal failure, occurred after prophylaxis with pyrimethamine/sulfadoxine combination in a 60-year-old female. Extensive diagnostic studies, before and after death, failed to find an etiology for this patient's renal deterioration, and pyrimethamine/sulfadoxine combination was presumed to be the cause (Selby et al, 1985).
    B) BLOOD IN URINE
    1) WITH THERAPEUTIC USE
    a) Hematuria may occur in patients receiving higher doses of pyrimethamine used for toxoplasmosis (Prod Info DARAPRIM(R) oral scored tablets, 2013).
    C) DYSURIA
    1) WITH POISONING/EXPOSURE
    a) CASE SERIES: During an outbreak of pyrimethamine toxicity in Pakistan, one patient developed dysuria (Khan Assir et al, 2014).

Reproductive

    3.20.1) SUMMARY
    A) Pyrimethamine and the combination sulfadoxine and pyrimethamine are classified as FDA pregnancy category C. In a parallel-group, open-label, individually randomized controlled superiority trial, limb anomalies were found in a small group of infants in Mali exposed over the second and third trimesters of pregnancy to either 2 or 3 doses of combination pyrimethamine/sulfadoxine for malaria prevention. Pyrimethamine was teratogenic in animal studies.
    3.20.2) TERATOGENICITY
    A) CONGENITAL ANOMALY
    a) Congenital anomalies of the limbs were observed in 0.6% of infants at birth in a parallel-group, open-label, individually randomized controlled superiority trial of pregnant women in Mali who received either 2 or 3 doses of intermittent preventive therapy for malaria with combination sulfadoxine 1500 mg and pyrimethamine 75 mg. Three instances of polydactyly were found in the 2-dose group (n=359) and one instance of clubfoot in the 3-dose group (n=362). Women in the 3-dose group were administered sulfadoxine-pyrimethamine prophylaxis between 16 and 24 weeks, 20 and 32 weeks, and no later than 36 weeks gestation, respectively; 2-dose participants received doses between 16 and 24 weeks and 25 and 36 weeks gestation, respectively (Maiga et al, 2011).
    B) ANIMAL STUDIES
    1) Reproduction animal studies showed teratogenicity in rats, hamsters, and miniature pigs. In rats, a significant increase in abnormalities such as cleft palate, brachygnathia, oligodactyly, and microphthalmia occurred following oral pyrimethamine doses 7 times the human dose for chemoprophylaxis of malaria or 2.5 times the human dose for toxoplasmosis. In addition, meningocele in hamsters and cleft palate in miniature pigs were observed when the animals were given oral doses 170 and 5 times the human doses, respectively (Prod Info Daraprim(R), 2003).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) The manufacturer has classified pyrimethamine as FDA pregnancy category C (Prod Info Daraprim(R), 2003).
    2) The manufacturer has classified the combination sulfadoxine and pyrimethamine as FDA pregnancy category C (Prod Info FANSIDAR(R) oral tablets, 2004).
    3) According to the manufacturer, women of childbearing potential should be warned against becoming pregnant during treatment with pyrimethamine (Prod Info Daraprim(R), 2003). Pyrimethamine, in combination with sulfadiazine and folinic acid, has been used in the treatment of fetal or congenital toxoplasmosis. Because of concerns about teratogenicity, this combination has been used in the second and third trimesters after infection has been confirmed (Phillips, 1998). The combination of pyrimethamine and sulfadoxine has also been used in the pregnant patient to treat chloroquine-resistent malaria tropica (Schaefer, 2001).
    4) One study suggests that multidose intermittent preventive treatment (IPTp), consisting of sulfadoxine/pyrimethamine combination, administered to primigravidae may interfere with the acquisition of protective immunity to pregnancy-associated malaria. The researchers recommend that IPTp be repeated in all subsequent pregnancies (Staalsoe et al, 2004).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) Pyrimethamine is excreted into human milk (Prod Info Daraprim(R), 2003), but is considered to be compatible with breastfeeding (Anon, 2001).
    2) Breastfeeding is contraindication during therapy with the combination of sulfadoxine and pyrimethamine (Prod Info FANSIDAR(R) oral tablets, 2004).
    3.20.5) FERTILITY
    A) FERTILITY INDEX
    1) The fertility index of rats treated with pyrimethamine was lowered when high doses were used, suggesting possible toxic effects on the whole organism and/or conceptuses (Prod Info Daraprim(R), 2003).

Carcinogenicity

    3.21.2) SUMMARY/HUMAN
    A) Prolonged pyrimethamine use was associated with two cases of cancer (granulocytic leukemia and reticulum cell sarcoma) in humans.
    3.21.3) HUMAN STUDIES
    A) CARCINOMA
    1) Pyrimethamine has been reported to be associated with two cases of cancer in humans. Chronic granulocytic leukemia occurred in a 51-year-old woman after using pyrimethamine for 2 years for toxoplasmosis. Reticulum cell sarcoma developed in a 56-year-old patient after using pyrimethamine for 14 months for toxoplasmosis (Prod Info Daraprim(R), 2003).
    3.21.4) ANIMAL STUDIES
    A) LACK OF EFFECT
    1) Although one source reported that pyrimethamine was not carcinogenic in female mice or in male or female rats (Prod Info Fansidar(R), , 2004), another source reported that pyrimethamine produced a significant increase in the number of lung tumors in mice given 25 mg/kg of pyrimethamine intraperitoneally (Prod Info Daraprim(R), 2003).

Genotoxicity

    A) An increase in the number of structural and numerical aberrations was found in the chromosomes analyzed from the bone marrow of rats dosed with pyrimethamine. Structural chromosome aberrations were induced by pyrimethamine in human blood lymphocytes cultured in vitro . Pyrimethamine was positive in the L5178Y/TK +/- mouse lymphoma assay without metabolic activation. However, it was found to be nonmutagenic in the Ames point mutation assay, the Rec assay, and the Escherichia coli WP2 assay (Prod Info Daraprim(R), 2003).
    B) Pyrimethamine has been shown to be mutagenic in laboratory animals and in human bone marrow following 3 or 4 consecutive daily doses totaling 200 to 300 mg (Prod Info Fansidar(R), , 2004).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) HEMATOLOGY FINDING
    1) WITH THERAPEUTIC USE
    a) Pyrimethamine is a folic acid antagonist and can cause hematologic abnormalities (including megaloblastic anemia, leukopenia, thrombocytopenia, and pancytopenia) seen with folic acid deficiency. This adverse effect is more common in patients who receive higher doses of pyrimethamine, such as those used to treat toxoplasmosis (Prod Info DARAPRIM(R) oral scored tablets, 2013; Braunwald et al, 1987; Ansdell et al, 1976; Fleming et al, 1974; Matthews et al, 1973; McGorven, 1964).
    b) Hyperpigmentation was reported in a 29-year-old HIV-negative woman receiving pyrimethamine 25 mg twice daily. Forty days from the initiation of therapy, the patient developed a generalized hyperpigmentation, especially on the periorbital, perioral, and palatal regions, and widespread bruises. Thrombocytopenia (9000/mm(3)) was evident. Pyrimethamine was discontinued, and platelets and folinic acid were administered. After 15 days, pigmentation began to regress, and within 6 months all clinical and laboratory findings returned to normal (Ozturk et al, 2002).
    c) Agranulocytosis occurred in one patient during malaria prophylaxis with Maloprim(R) (12.5 mg pyrimethamine/100 mg dapsone). A previously healthy 52-year-old man received Maloprim(R) 1 tablet daily for 8 weeks, with the last dose ingested 5 days prior to hospitalization. The patient had not taken any other drugs in the 6 months prior to the onset of agranulocytosis. Two to five days before admission the patient complained of general malaise, sore throat, perianal tenderness, fever with rigors, nausea, diarrhea, and cough. A blood count showed a hemoglobin of 13.7 grams/dL, a white blood cell count of 0.27 x10(9)/L and a platelet count of 333 x10(9)/L. No granulocytes were present. The patient improved clinically and objectively after 1 to 2 weeks of protective isolation, intravenous antibiotics and supplemental granulocyte transfusions (Booth et al, 1984).
    d) PYRIMETHAMINE/SULFADOXINE combination has been associated with agranulocytosis and granulocytopenia (Phillips-Howard & West, 1990).
    2) WITH POISONING/EXPOSURE
    a) Bone marrow depression may occur manifested by neutropenia, thrombocytopenia, and macrocytic/megaloblastic anemia after chronic overdose of pyrimethamine (Akinyanju et al, 1973).
    b) CASE SERIES: During an outbreak of pyrimethamine toxicity in Pakistan, leukopenia (median WBC: 2.3 x 10(9)/L; range: 0.1 x 10(9)/L to 16 x 10(9)/L) developed in 96 (82.1%) of the 664 patients with ischemic heart disease who received isosorbide mononitrate contaminated with about 50 mg of pyrimethamine. Thrombocytopenia (median platelet count: 18 x 10(9)/L; range: 0 x 10(9)/L to 318 x 10(9)/L) and anemia (median hemoglobin concentration: 109 g/L; range: 58 to 169) developed in 113 (96.6%) and 80 (68.4%) of the 664 patients, respectively. Trilineage dysplasia and severe megaloblastosis were revealed by bone marrow examination (Khan Assir et al, 2014).
    c) CASE REPORT: A 4-year-old child who received 50 mg weekly for 6 months developed megaloblastic anemia, requiring folate therapy and transfusions (Akinyanju et al, 1973).
    d) CASE REPORT: A 7-month-old infant developed loss of consciousness and generalized seizures after receiving 30 mg of pyrimethamine instead of the 3 mg prescribed (10 times the usual dose) over 10 days for congenital toxoplasmosis. Laboratory examination revealed mild anemia (Hb, 9.3 g/100 mL; RBC, 3.8 x 10(6)/mm(3)) without megaloblastosis. Following treatment with diazepam (intrarectal, then 3 mg/day), she recovered completely and was discharged on hospital day 7 (Tracqui et al, 1993).
    B) BLEEDING
    1) WITH POISONING/EXPOSURE
    a) CASE SERIES: During an outbreak of pyrimethamine toxicity in Pakistan, bleeding developed in 95% of the 664 patients with ischemic heart disease who received isosorbide mononitrate contaminated with about 50 mg of pyrimethamine. Hemorrhagic effects included epistaxis (68.4%), melena (51.3%), gum bleeding (49.6%), hematemesis (40.2%), petechiae (30.8%), hematochezia (29.1%), purpura (19.7%), gross hematuria (17.1%), hemoptysis (11.1%), bilateral subconjunctival hemorrhages (1.6%), bleeding from ear (0.8%), intraperitoneal bleeding (0.8%), and periorbital hematoma (0.8%) (Khan Assir et al, 2014).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) DERMATOLOGICAL FINDING
    1) WITH THERAPEUTIC USE
    a) PYRIMETHAMINE/SULFADOXINE: Serious cutaneous reactions, including erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported with pyrimethamine/sulfadoxine combination. Some cases have resulted in fatalities (Phillips-Howard & West, 1990; Steffen & Somaini, 1986; Bradley et al, 1985; Anon, 1985; Miller et al, 1986). These reactions have been associated only with multiple doses of pyrimethamine-sulfadoxine, and have not been reported with single-dose pyrimethamine/sulfadoxine as used in the treatment of malaria (Anon, 1985).
    2) WITH POISONING/EXPOSURE
    a) Hyperpigmentation (diffuse or partial involving face, hands, feet, abdomen, axillae and groin), maculopapular rash, petechiae, purpura, ecchymosis, xerosis, pruritic scratch marks, necrolysis of epidermis were reported during an outbreak of pyrimethamine toxicity in Pakistan after 664 patients with ischemic heart disease received isosorbide mononitrate contaminated with about 50 mg of pyrimethamine (Khan Assir et al, 2014).
    B) ERUPTION
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: Pyrimethamine prophylaxis against toxoplasmic encephalitis has caused rash in HIV-infected patients, with an incidence of approximately 7%. In this double-blind placebo-controlled trial, 20 of 274 patients developed rashes (urticarial and morbilliform) within a median of 13 days of pyrimethamine therapy. Discontinuation of the drug resolved symptoms (Rousseau et al, 1997).
    C) ITCHING OF SKIN
    1) WITH POISONING/EXPOSURE
    a) CASE SERIES: During an outbreak of pyrimethamine toxicity in Pakistan, pruritus developed in 40 (34.2%) of the 664 patients with ischemic heart disease who received isosorbide mononitrate contaminated with about 50 mg of pyrimethamine (Khan Assir et al, 2014).
    D) HYPERPIGMENTATION OF SKIN
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: Hyperpigmentation was reported in a 29-year-old HIV-negative female receiving pyrimethamine 25 mg twice daily. Forty days from the initiation of therapy, the patient developed a generalized hyperpigmentation, especially on the periorbital, perioral, and palatal regions, and widespread bruises. Thrombocytopenia (9000/mm(3)) was evident. Pyrimethamine was discontinued, and platelets and folinic acid were administered. After 15 days, pigmentation began to regress, and within 6 months all clinical and laboratory findings returned to normal (Ozturk et al, 2002).
    2) WITH POISONING/EXPOSURE
    a) CASE SERIES: During an outbreak of pyrimethamine toxicity in Pakistan, skin hyperpigmentation developed in 71 (60.7%) of the 664 patients with ischemic heart disease who received isosorbide mononitrate contaminated with about 50 mg of pyrimethamine (Khan Assir et al, 2014).
    E) STEVENS-JOHNSON SYNDROME
    1) WITH THERAPEUTIC USE
    a) Stevens-Johnson Syndrome may occur following pyrimethamine therapy, particularly when given with a sulfonamide (Prod Info DARAPRIM(R) oral scored tablets, 2013).
    b) PYRIMETHAMINE/SULFADOXINE: Pyrimethamine in combination with sulfadoxine (Fansidar(R)) has caused Stevens-Johnson Syndrome (SJS). The incidence is estimated to be 1.1 cases per million patients prescribed pyrimethamine/sulfadoxine combination. The average age of the patients was 36 years and 53% were female. The fatality rate was 9% in patients with SJS (Sturchler et al, 1993; Miller et al, 1986a).
    c) Stevens-Johnson syndrome has been reported in patients with acquired immunodeficiency syndrome (AIDS) after prophylaxis with pyrimethamine/sulfadoxine combination. Some authors feel that patients with AIDS may be at increased risk of adverse reactions to sulfonamides (Navin et al, 1985; Jaffe et al, 1983).
    d) CASE REPORTS
    1) PYRIMETHAMINE/SULFADOXINE: At least 6 cases of Stevens-Johnson syndrome with pyrimethamine/sulfadoxine have been reported (Phillips-Howard & West, 1990). In one case Stevens-Johnson syndrome occurred after a 5-year-old boy took pyrimethamine/sulfadoxine and chloroquine for malaria prophylaxis. This patient eventually died as a result of the syndrome (Bamber et al, 1986). Another case occurred in a 5-year-old boy whose mother accidentally administered an excessive dose. Because of extensive ocular involvement, the patient required a corneal transplant and his visual acuity was extremely poor (Phillips-Howard et al, 1989).
    2) PYRIMETHAMINE/SULFADOXINE: Stevens-Johnson Syndrome occurred in a 50-year-old male receiving Fansidar(R) (sulfadoxine-pyrimethamine) for approximately 3 weeks for anti-malarial prophylaxis. Numerous complications occurred requiring 3 months of hospitalization, including pneumonia, sterile pleural effusion and binocular ulcerative keratitis secondary to pneumococcus. Lymphocyte-transformation test indicated that pyrimethamine was the causative agent in this case (Hornstein & Ruprecht, 1982).
    F) ERYTHEMA MULTIFORME
    1) WITH THERAPEUTIC USE
    a) Erythema multiforme may occur following pyrimethamine therapy, particularly when given with a sulfonamide (Prod Info DARAPRIM(R) oral scored tablets, 2013).
    b) PYRIMETHAMINE/SULFADOXINE: Erythema multiforme was reported in a 30-year-old man after prophylaxis with pyrimethamine/sulfadoxine combination. Severe, extensive bullous eruptions developed on the patient's hands, feet, limbs, and trunk after 2 doses of pyrimethamine/sulfadoxine combination. The patient had no previous history of sulfonamide hypersensitivity and there was no evidence of a recent herpes simplex or mycoplasma pneumoniae infection. Recovery was full and uneventful after a course of oral corticosteroids (Adams et al, 1985).
    G) LYELL'S TOXIC EPIDERMAL NECROLYSIS, SUBEPIDERMAL TYPE
    1) WITH THERAPEUTIC USE
    a) Toxic epidermal necrolysis may occur following pyrimethamine therapy, particularly when given with a sulfonamide (Prod Info DARAPRIM(R) oral scored tablets, 2013).
    b) PYRIMETHAMINE/SULFADOXINE: Pyrimethamine in combination with sulfadoxine (Fansidar (R)) has been reported to cause toxic epidermal necrolysis (TEN). The incidence of TEN is estimated to be 1.1 cases per million patients prescribed pyrimethamine/sulfadoxine combination. The average age of the patients was 36 years and 53% were female. The fatality rate in patients diagnosed with TEN was 36% (Sturchler et al, 1993a).
    c) PYRIMETHAMINE/SULFADOXINE: Fatal toxic epidermal necrolysis occurred in a 48-year-old male with AIDS receiving pyrimethamine/sulfadoxine (25 mg/500 mg) once weekly for Pneumocystis carinii pneumonia prophylaxis. After approximately 6 weeks of therapy, the patient developed an erythematous macular rash on the neck which worsened over the subsequent 2 weeks to widespread erythema, blisters and loss of skin in sheets. The patient died despite supportive therapy (Raviglione et al, 1988a).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) MUSCLE PAIN
    1) WITH POISONING/EXPOSURE
    a) CASE SERIES: During an outbreak of pyrimethamine toxicity in Pakistan, myalgia developed in 23 (19.7%) of the 664 patients with ischemic heart disease who received isosorbide mononitrate contaminated with about 50 mg of pyrimethamine (Khan Assir et al, 2014).
    B) JOINT PAIN
    1) WITH POISONING/EXPOSURE
    a) CASE SERIES: During an outbreak of pyrimethamine toxicity in Pakistan, arthralgia developed in 20 (17.1%) of the 664 patients with ischemic heart disease who received isosorbide mononitrate contaminated with about 50 mg of pyrimethamine (Khan Assir et al, 2014).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) HYPERSENSITIVITY REACTION
    1) WITH THERAPEUTIC USE
    a) Anaphylaxis and other hypersensitivity phenomena (eg, Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme) have been reported occasionally, particularly when given with a sulfonamide (Prod Info DARAPRIM(R) oral scored tablets, 2013).
    b) PYRIMETHAMINE/SULFADOXINE: Hypersensitivity pneumonitis occurred in a 64-year-old male after approximately one month of pyrimethamine/sulfadoxine combination therapy. The patient developed an influenza-like illness after approximately 1 month of pyrimethamine/sulfadoxine combination administration; pyrimethamine/sulfadoxine combination was initiated 2 weeks prior to departure from Canada, and continued for two weeks in Kenya and then several days in England, where the patient developed an influenza-like illness. Four days later, the patient travelled to Switzerland, where he presented with symptoms of pneumonia. The patient deteriorated rapidly, developing respiratory failure and requiring mechanical ventilation for 4 weeks. Recovery occurred slowly with steroid therapy (McCormack & Morgan, 1987).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor vital signs, hepatic enzymes and renal function after significant overdose.
    C) Monitor serum electrolytes in patients with severe vomiting.
    D) Monitor serial CBC with differential and platelet count in symptomatic patients. Daily monitoring of CBC is recommended for several weeks after pyrimethamine overdose due to its long half-life.
    4.1.2) SERUM/BLOOD
    A) Monitor serial CBC with differential and platelet count in symptomatic patients. Daily monitoring of CBC is recommended for several weeks after pyrimethamine overdose due to its long half-life (Prod Info DARAPRIM(R) oral tablets, 2003).

Methods

    A) MASS SPECTROMETRY
    1) Mass spectrometry was used to measure pyrimethamine plasma concentration to verify poisoning in one patient (Vereczkey et al, 1998).
    B) HIGH PERFORMANCE LIQUID CHROMATOGRAPHY (HPLC)
    1) HPLC was used to measure pyrimethamine and sulfadoxine concentrations in plasma and urine samples. This HPLC method had a lower limit of detection with 0.050 mcmol/L for pyrimethamine and 5 mcmol/L for sulfadoxine and acetylsulfadoxine (Lindberg et al, 1986).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients should be admitted for severe vomiting, electrolyte abnormalities, persistent cardiac dysrhythmias, mental status changes, myelosuppression, seizures, and respiratory failure. Patients should remain admitted until they are clearly improving and clinically stable.
    6.3.1.2) HOME CRITERIA/ORAL
    A) A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with a deliberate overdose, and those who are symptomatic, need to be monitored for several hours. Neurologic symptoms usually occur rapidly (within 30 minutes to 2 hours) following ingestion (Prod Info DARAPRIM(R) oral scored tablets, 2013). Patients that remain asymptomatic can be discharged. However, due to the long-half-life of pyrimethamine (96 hours), daily monitoring of peripheral blood counts is recommend for a few weeks after exposure until all hematologic parameters are normal (Prod Info DARAPRIM(R) oral scored tablets, 2013).

Monitoring

    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor vital signs, hepatic enzymes and renal function after significant overdose.
    C) Monitor serum electrolytes in patients with severe vomiting.
    D) Monitor serial CBC with differential and platelet count in symptomatic patients. Daily monitoring of CBC is recommended for several weeks after pyrimethamine overdose due to its long half-life.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Prehospital gastrointestinal decontamination is generally not recommended because of the potential for CNS depression or persistent seizures and subsequent aspiration.
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) SUPPORT
    1) MANAGEMENT OF MILD TO MODERATE TOXICITY
    a) Treatment is symptomatic and supportive.
    2) MANAGEMENT OF SEVERE TOXICITY
    a) Treatment is symptomatic and supportive. Treat seizures with IV benzodiazepines; barbiturates or propofol may be needed if seizures persist or recur. Myelosuppression has been reported. Monitor serial CBC with differential and platelet count. For severe neutropenia, administer colony stimulating factor (eg; filgrastim, sargramostim). Transfusions as needed for severe thrombocytopenia, bleeding. In patients with acute allergic reaction, oxygen therapy, bronchodilators, diphenhydramine, corticosteroids, vasopressors and epinephrine may be required.
    B) MONITORING OF PATIENT
    1) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    2) Monitor vital signs, hepatic enzymes and renal function after significant overdose.
    3) Monitor serum electrolytes in patients with severe vomiting.
    4) Monitor serial CBC with differential and platelet count in symptomatic patients. Daily monitoring of CBC is recommended for several weeks after pyrimethamine overdose due to its long half-life (Prod Info DARAPRIM(R) oral tablets, 2003).
    C) SEIZURE
    1) SUMMARY
    a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
    b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
    c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).
    2) DIAZEPAM
    a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
    b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .
    3) NO INTRAVENOUS ACCESS
    a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
    b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).
    4) LORAZEPAM
    a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
    b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
    c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2009; Chin et al, 2008).
    5) PHENOBARBITAL
    a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
    b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
    c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
    d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
    e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
    f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).
    6) OTHER AGENTS
    a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):
    1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
    2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
    3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
    4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).
    7) RECURRING SEIZURES
    a) If seizures are not controlled by the above measures, patients will require endotracheal intubation, mechanical ventilation, continuous EEG monitoring, a continuous infusion of an anticonvulsant, and may require neuromuscular paralysis and vasopressor support. Consider continuous infusions of the following agents:
    1) MIDAZOLAM: ADULT DOSE: An initial dose of 0.2 mg/kg slow bolus, at an infusion rate of 2 mg/minute; maintenance doses of 0.05 to 2 mg/kg/hour continuous infusion dosing, titrated to EEG (Brophy et al, 2012). PEDIATRIC DOSE: 0.1 to 0.3 mg/kg followed by a continuous infusion starting at 1 mcg/kg/minute, titrated upwards every 5 minutes as needed (Loddenkemper & Goodkin, 2011).
    2) PROPOFOL: ADULT DOSE: Start at 20 mcg/kg/min with 1 to 2 mg/kg loading dose; maintenance doses of 30 to 200 mcg/kg/minute continuous infusion dosing, titrated to EEG; caution with high doses greater than 80 mcg/kg/minute in adults for extended periods of time (ie, longer than 48 hours) (Brophy et al, 2012); PEDIATRIC DOSE: IV loading dose of up to 2 mg/kg; maintenance doses of 2 to 5 mg/kg/hour may be used in older adolescents; avoid doses of 5 mg/kg/hour over prolonged periods because of propofol infusion syndrome (Loddenkemper & Goodkin, 2011); caution with high doses greater than 65 mcg/kg/min in children for extended periods of time; contraindicated in small children (Brophy et al, 2012).
    3) PENTOBARBITAL: ADULT DOSE: A loading dose of 5 to 15 mg/kg at an infusion rate of 50 mg/minute or lower; may administer additional 5 to 10 mg/kg. Maintenance dose of 0.5 to 5 mg/kg/hour continuous infusion dosing, titrated to EEG (Brophy et al, 2012). PEDIATRIC DOSE: A loading dose of 3 to 15 mg/kg followed by a maintenance dose of 1 to 5 mg/kg/hour (Loddenkemper & Goodkin, 2011).
    4) THIOPENTAL: ADULT DOSE: 2 to 7 mg/kg, at an infusion rate of 50 mg/minute or lower. Maintenance dose of 0.5 to 5 mg/kg/hour continuous infusing dosing, titrated to EEG (Brophy et al, 2012)
    b) Endotracheal intubation, mechanical ventilation, and vasopressors will be required (Brophy et al, 2012) and consultation with a neurologist is strongly advised.
    c) Neuromuscular paralysis (eg, rocuronium bromide, a short-acting nondepolarizing agent) may be required to avoid hyperthermia, severe acidosis, and rhabdomyolysis. If rhabdomyolysis is possible, avoid succinylcholine chloride, because of the risk of hyperkalemic-induced cardiac dysrhythmias. Continuous EEG monitoring is mandatory if neuromuscular paralysis is used (Manno, 2003).
    D) FOLIC ACID
    1) Blood dyscrasias, such as leukopenia or neutropenia, megaloblastic anemia, and thrombocytopenia may occur following pyrimethamine use. Treat patients with folic acid or leucovorin (5 to 15 mg daily orally, IV, or IM) to prevent hematologic toxicity. Treatment should be given within 2 hours, if possible, of overdose to avoid or minimize the hematopoietic effects that can develop (Prod Info DARAPRIM(R) oral scored tablets, 2013).
    E) MYELOSUPPRESSION
    1) There is little data on the use of hematopoietic colony stimulating factors to treat neutropenia after drug overdose or idiosyncratic reactions. These agents have been shown to shorten the duration of severe neutropenia in patients receiving cancer chemotherapy (Hartman et al, 1997; Stull et al, 2005). They have also been used to treat agranulocytosis induced by nonchemotherapy drugs (Beauchesne & Shalansky, 1999). They may be considered in patients with severe neutropenia who have or are at significant risk for developing febrile neutropenia.
    a) Filgrastim: The usual starting dose in adults is 5 micrograms/kilogram/day by intravenous infusion or subcutaneous injection (Prod Info NEUPOGEN(R) injection, 2006).
    b) Sargramostim: Usual dose is 250 micrograms/square meter/day infused IV over 4 hours (Prod Info LEUKINE(R) injection, 2006).
    c) Monitor CBC with differential.
    2) Transfusion of platelets and/or packed red cells may be needed in patients with severe thrombocytopenia, anemia or hemorrhage.

Enhanced Elimination

    A) HEMODIALYSIS
    1) Hemodialysis is UNLIKELY to be of value because of the high degree of protein binding of pyrimethamine.

Abstracts

Case Reports

    A) PEDIATRIC
    1) Overdose in a 14-month-old child who accidentally ingested 450 mg pyrimethamine has been reported and was associated with severe adverse effects including cyanosis, apnea, coma, seizures, hyperpyrexia, blindness, deafness, ataxia, and tachycardia. Blindness and deafness resolved slowly with residual mental retardation on long-term follow-up, likely secondary to anoxic injury (Akinyanju et al, 1973).

Range Of Toxicity

Summary

    A) TOXICITY: Ingestion of 300 mg or more can produce toxicity, including gastrointestinal effects (eg; abdominal pain, nausea, severe vomiting). In severe cases, this may be followed by excitability, generalized and prolonged seizures, respiratory depression, circulatory collapse and death. PEDIATRIC: Fatalities have occurred in young children less than 2 years old following doses of 375 to 1625 mg. NEWBORN: A 7-day-old newborn was prescribed sulfadiazine 100 mg/kg/day in 3 divided doses (instead of 1 mg/kg/day), pyrimethamine 100 mg/kg/day in 3 divided doses, and folinic acid 50 mg/week in 2 divided doses. The pyrimethamine dosing error was discovered 3 days later after the patient received 4 doses of pyrimethamine. He developed moderate cholestasis, loss of appetite, vomiting, and seizures. Following supportive care, he recovered and was discharged a week after hospitalization.
    B) THERAPEUTIC DOSE: ADULT: Varies by indication; 25 to 75 mg/day orally. PEDIATRIC: Varies by indication; TOXOPLASMOSIS: 1 mg/kg/day orally in 2 equal daily doses; may be reduced after 2 to 4 days to half of the initial dose for about a month. ACUTE MALARIA: Monotherapy in semi-immune patients aged 4 to 10 years: 25 mg/day orally for 2 days. MALARIA CHEMOPROPHYLAXIS: Infants and children under age 4 years: 6.25 mg (one-fourth tablet) orally once weekly for at least 10 weeks. Children aged 4 to 10 years: 12.5 mg (one-half tablet) orally once weekly for at least 10 weeks. Children aged 10 years and older: 25 mg (one tablet) orally once weekly for at least 10 weeks.

Therapeutic Dose

    7.2.1) ADULT
    A) TOXOPLASMOSIS
    1) INITIAL TREATMENT: The recommended starting dose is 50 to 75 mg/day orally plus 1 to 4 g/day of sulfadoxine or another sulfonamide of the sulfapyrimidine type for 1 to 3 weeks. The dose may be reduced to about half of the initial dose for another 4 to 5 weeks (Prod Info DARAPRIM(R) oral scored tablets, 2013).
    B) ACUTE MALARIA
    1) INITIAL CONTROL AND SUPPRESSION OF NON-FALCIPARUM MALARIA: 25 mg/day orally for 2 days with a sulfonamide (Prod Info DARAPRIM(R) oral scored tablets, 2013).
    2) MONOTHERAPY IN SEMI-IMMUNE PATIENTS: 50 mg/day orally for 2 days (Prod Info DARAPRIM(R) oral scored tablets, 2013).
    C) MALARIA CHEMOPROPHYLAXIS
    1) The recommended dose is 25 mg orally once weekly for at least 10 weeks (Prod Info DARAPRIM(R) oral scored tablets, 2013).
    7.2.2) PEDIATRIC
    A) TOXOPLASMOSIS
    1) INITIAL TREATMENT: The recommended starting dose is 1 mg/kg/day orally in 2 equal daily doses. The dose may be reduced after 2 to 4 days to half of the initial dose for about a month. The usual sulfonamide dosage for children is administered with pyrimethamine (Prod Info DARAPRIM(R) oral scored tablets, 2013).
    B) ACUTE MALARIA
    1) MONOTHERAPY IN SEMI-IMMUNE PATIENTS AGED 4 to 10 YEARS: 25 mg/day orally for 2 days (Prod Info DARAPRIM(R) oral scored tablets, 2013).
    C) MALARIA CHEMOPROPHYLAXIS
    1) INFANTS AND CHILDREN UNDER AGE 4 YEARS: The recommended dose is 6.25 mg (one-fourth tablet) orally once weekly for at least 10 weeks (Prod Info DARAPRIM(R) oral scored tablets, 2013).
    2) CHILDREN AGED 4 TO 10 YEARS: The recommended dose is 12.5 mg (one-half tablet) orally once weekly for at least 10 weeks (Prod Info DARAPRIM(R) oral scored tablets, 2013).
    3) CHILDREN AGED 10 YEARS AND OLDER: The recommended dose is 25 mg (one tablet) orally once weekly for at least 10 weeks (Prod Info DARAPRIM(R) oral scored tablets, 2013).

Minimum Lethal Exposure

    A) CASE REPORTS
    1) Fatalities have been reported in children after the following pyrimethamine doses:
    a) 375 mg in a 20-month-old (Taylor, 1953)
    b) 625 to 750 mg in a 1-year-old (Chance, 1956)
    c) 1625 mg in a 16-month-old (Davies, 1956)
    d) 400 mg in a 20-month-old (COVELL et al, 1953)
    e) 400 mg in a 28-month-old (Gunther, 1954)
    2) PYRIMETHAMINE/SULFADOXINE
    a) ADULT: A 48-year-old HIV-infected man developed toxic epidermal necrolysis which progressed to cardiopulmonary arrest and death following 2 months of weekly prophylaxis with pyrimethamine 25 mg and sulfadoxine 500 mg (Raviglione et al, 1988).
    B) CASE SERIES
    1) During an outbreak of pyrimethamine toxicity in Pakistan, 664 patients with ischemic heart disease received isosorbide mononitrate contaminated with about 50 mg of pyrimethamine. Adverse effects included bleeding, skin hyperpigmentation, rash, pruritus, diarrhea, fever, abdominal pain, cough, sore throat, irritability, myalgia, arthralgia, oral ulcers, leukopenia, thrombocytopenia, and anemia. All deaths (n=151; 23%) occurred before the contamination was detected and did not receive therapy with calcium folinate. Age greater than 57 years, hypotension, and leukocyte count less than 1.5 x 10(9)/L were the main predictors of mortality (Khan Assir et al, 2014).

Maximum Tolerated Exposure

    A) PEDIATRIC
    1) Doses of 300 mg, 450 mg, and 625 mg in children aged 27 months, 14 months, and 2.5 years, respectively, have resulted in seizures, with full or partial recovery (Guignard, 1965; Akinyanju et al, 1973; Davies, 1956).
    2) Ingestion of 375 mg (23.8 mg/kg) by a 3-year-old child resulted in repeated vomiting but no other symptoms (Abbott & Ali Hamdl, 1953).
    3) PYRIMETHAMINE/SULFADIAZINE: A 7-day-old newborn with asymptomatic congenital toxoplasmosis was prescribed sulfadiazine 100 mg/kg/day in 3 divided doses, pyrimethamine 100 mg/kg/day in 3 divided doses (instead of 1 mg/kg/day), and folinic acid 50 mg/week in 2 divided doses. The pyrimethamine dosing error was discovered 3 days later after the patient received 4 doses of pyrimethamine. Laboratory results revealed isolated, moderate cholestasis (total bilirubin = 74 mcmol/L; conjugated bilirubin 40 mcmol/L). At this time, pyrimethamine and sulfadiazine were discontinued and folinic acid dose was increased to 25 mg/day. About 48 hours after receiving the first overdose, he developed partial seizures which resolved after receiving 1 dose of phenobarbital. He also had loss of appetite and vomiting that resolved 5 days later. The cholestasis resolved spontaneously and he was discharged after 1 week of hospitalization. The antiparasitic treatment was restarted and on 3-month followup, the child was doing well and tolerated the treatment (Genuini et al, 2011).
    4) A 7-month-old infant developed irritability, vomiting, loss of consciousness and generalized seizures after receiving 30 mg of pyrimethamine instead of the 3 mg prescribed (10 times the usual dose) over 10 days for congenital toxoplasmosis. Following treatment with diazepam (intrarectal, then 3 mg/day), she recovered completely and was discharged on hospital day 7 (Tracqui et al, 1993).
    B) ADULT
    1) Ingestion of 300 mg or more can produce toxicity, including gastrointestinal effects (eg; abdominal pain, nausea, severe vomiting). In severe cases, this may be followed by excitability, generalized and prolonged seizures, respiratory depression, circulatory collapse and death (Prod Info DARAPRIM(R) oral scored tablets, 2013).
    2) Ingestion of 350 mg over 48 hours in an adult resulted in seizures; the patient had a prior history of seizures (Grisham, 1962).
    3) CASE SERIES: During an outbreak of pyrimethamine toxicity in Pakistan, 664 patients with ischemic heart disease received isosorbide mononitrate contaminated with about 50 mg of pyrimethamine. Adverse effects included bleeding, skin hyperpigmentation, diarrhea, fever, abdominal pain, cough, pruritus, sore throat, irritability, myalgia, arthralgia, oral ulcers, leukopenia, thrombocytopenia, and anemia. All deaths (n=151; 23%) occurred before the contamination was detected and did not receive therapy with calcium folinate. Age greater than 57 years, hypotension, and leukocyte count less than 1.5 x 10(9)/L were the main predictors of mortality (Khan Assir et al, 2014).

Serum Plasma Blood Concentrations

    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) Plasma concentrations of pyrimethamine and sulfadoxine were 5 x 10(3) and 1 x 10(6) nanomoles/liter, respectively in four patients following 19 days of pyrimethamine 25 mg/sulfadoxine 500 mg daily. All patients suffered minimal toxic effects (Lindberg et al, 1986).
    2) Plasma pyrimethamine levels in patients with bone marrow toxicity were 1.34 times as high as patients without hematopoietic dysfunction (0.16 to 0.44 mg/dL) (Kaufman & Caldwell, 1959).
    3) A 7-month-old infant developed loss of consciousness and generalized seizures a week after receiving 30 mg of pyrimethamine instead of the 3 mg prescribed (10 times the usual dose) over 10 days. The following time-related plasma and urine levels of pyrimethamine were obtained (Tracqui et al, 1993):
    1) 1 hour - Plasma : 6.22 mcg/mL
    2) 4 hours - Plasma: 5.69 mcg/mL; Urine: 7.6 mcg/mL
    3) 22 hours - Plasma: 5.67 mcg/mL; Urine: 6.66 mcg/mL
    4) 46 hours - Plasma: 3.98 mcg/mL; Urine: 4.03 mcg/mL
    5) 168 hours - Plasma: 0.32 mcg/mL; Urine: 0.34 mcg/mL

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Pyrimethamine is a folic acid antagonist which is used as an antiparasitic agent. The activity of pyrimethamine is limited primarily to plasmodia and Toxoplasma gondii (Prod Info DARAPRIM(R) oral scored tablets, 2013). Pyrimethamine binds to and reversibly inhibits the protozoal enzyme dihydrofolate reductase, selectively blocking conversion of dihydrofolic acid to its functional form, tetrahydrofolic acid. This depletes folate, an essential cofactor in the biosynthesis of nucleic acids, resulting in interference with protozoal nucleic acid and protein production. Protozoal dihydrofolate reductase is many times more tightly bound by pyrimethamine than the corresponding mammalian enzyme (Prod Info Daraprim, 98; Gillis, 1998).

Physicochemical

Molecular Weight

    A) 248.71 (Prod Info DARAPRIM(R) oral tablets, 2003)

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